This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Introduction

Dr. Pant: Hello, and welcome to Emerging Therapies for Patients with HER2-Positive Gastroesophageal Adenocarcinoma and Biliary Tract Cancer. I'm Dr. Shubham Pant. I'm a Professor of GI Medical Oncology at the MD Anderson Cancer Center in Houston, Texas. And with me is Dr. Amit Mahipal. Please introduce yourself.

Dr. Amit Mahipal (Case Comprehensive Cancer Center): Hi, everyone. I'm a Professor of GI Medical Oncology at Case Western Reserve University and University Hospitals

Dr. Pant: Today, we are going to discuss a brief overview of biliary tract cancers and gastroesophageal adenocarcinoma. I'm going to discuss the key clinical takeaways from a think tank and the survey with Amit. We're also going to discuss a couple of very important case reports, which is a briefcase in biliary tract cancer and a briefcase in gastroesophageal adenocarcinoma.

We're also going to discuss emerging data sets affecting clinical practice, persistent needs identified in recent serial assessment surveys. Also going to discuss challenges faced by healthcare professionals in the management of patients with biliary tract cancer and/or gastroesophageal adenocarcinoma. To kick off this podcast, Amit, can you give a brief overview of what gastroesophageal adenocarcinoma is?

Dr. Mahipal: Sure. So gastroesophageal adenocarcinoma is a group of diseases that originates either in the stomach, esophagus or gastroesophageal junction. And the anatomy matters specifically in terms of surgical options, especially if these patients are diagnosed at the early stage. The way we treat lower esophageal or gastroesophageal junction cancer is a little bit different than gastric cancer.

However, from a practical perspective and basically from the systemic therapy perspective for patients with advanced gastroesophageal adenocarcinomas, they're treated regardless of if they originate in stomach or in the esophagus or GE junction. So there's no difference. So that's why we call them gastroesophageal adenocarcinoma.

Unfortunately for patients with advanced GEA, there is a very poor prognosis. And we have very low five-year survival rate, in single digits basically. So there's a lot of room for improvement. And recently, there has been a lot of biomarker development, which is guiding our first-line treatment for advanced gastroesophageal adenocarcinoma.

Shubham, I'll ask you, if you could describe what biliary tract cancer means?

Dr. Pant: Just like gastroesophageal adenocarcinoma, the majority of biliary tract cancers are unfortunately found in stage IV, where the prognosis is poor. Currently for the frontline therapy for advanced cancers, we treat them with gemcitabine-cisplatin with a checkpoint inhibitor, normally either durvalumab or pembrolizumab.

And in the second-line setting, if they do not have any targetable alterations, we normally give them chemotherapy. But the exciting thing recently in biliary tract cancer has been the advent of targeted therapies. So, we do the next-generation sequencing. And there are different targeted therapy options.

In our podcast today, we are also discussing really interesting newer therapies for biliary tract cancer, specifically for HER2-positive or HER2-amplified disease. And we're going to discuss a few options which have recently been FDA-approved for this disease. So five-year outcomes are not great, but we have a lot of emerging options for our patients.

Now I am going to discuss some survey responses from healthcare providers who treat patients with biliary tract cancer and/or gastroesophageal adenocarcinoma.

The first question we asked was, which specific cancer type do you think is commonly associated with HER2-positivity? And 43 respondents gave a response and the different answers were: gallbladder cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, gastroesophageal cancer, none of the above, or I'm not sure.

And the most commonly picked was gastroesophageal adenocarcinoma. And the second most commonly picked was gallbladder cancer. I think both are correct.

The second question was, in your opinion, which of the following indicates HER2-positivity for patients with BTC and/or GEA? And folks answered either it's IHC 3+ or IHC 2+ and FISH-positive.

Amit, I'm going to pause here, ask you about your thoughts on this answer of IHC 3+. What do you think about IHC 2+ and FISH-positive as it pertains to gastroesophageal adenocarcinoma and for biliary tract cancers?

Dr. Mahipal: Sure. So I think from the FDA approval perspective, at least for the gastroesophageal cancer. So patients who are IHC 3+, they are considered HER2-positive. For patients who are IHC 2+, they require additional testing called FISH testing. And if they are FISH-positive, then they are clubbed into this bucket of being HER2-positive and can be treated as per HER2-directed therapies.

Most of the pathology, there is a like a, I would say, reflex testing. So there is IHC 2+. They do automatically should get FISH testing. But if that's not the case, want to make sure that IHC 2+ is not considered positive. So those patients should get FISH testing and then treated with HER2-directed therapy if they are FISH-positive.

Dr. Pant: The third question was, which subtype of BTC do you think has the highest level of HER2 expression? And the answers were: gallbladder cancer, extrahepatic cholangiocarcinoma, intrahepatic, none of the above, or I'm not sure. Majority of respondents said I'm not sure, which is understandable because we have to remember gallbladder cancer and biliary tract cancers are rare cancers overall. We don't see a lot of them in the US.

But to answer the question for our respondents, the number one is gallbladder cancer actually, when the HER2-positivity can be up to 30%. So if you have a patient with advanced gallbladder cancer, definitely do test them for HER2-positivity. Technically, you should do that for all biliary tract cancer patients, but gallbladder cancer specifically has the highest level of HER2 expression.

Coming to our fourth question, we asked, in your clinical practice, are you retesting for HER2 status before recommending the next line of therapy after disease progression for your patients who have previously been exposed to HER2-targeted therapies? And the majority, 55%, said yes.

Amit, what do you think about this as far as BTC is concerned and GEA is concerned?

Dr. Mahipal:Yeah, I think retesting for HER2 before starting next line of therapy is very important, especially in gastroesophageal junction cancer. I would say it's important when you're treating someone with a HER2-directed therapy. So we'll talk about first-line treatment for gastroesophageal cancer. But typically for patients with advanced gastroesophageal cancer who are HER2-positive, we tend to treat them with HER2-directed therapy plus chemotherapy.

And if these patients progress, at that point, we would definitely recommend testing for HER2 status again. And then if they are HER2-positive, then consider appropriate anti-HER2 therapy.

In terms of BTC, I mean we don't have any anti-HER2 therapy yet approved in the first-line setting. So if they’re HER2-positive at baseline and then you treat them with chemoimmunotherapy as a standard of care first-line therapy, I don't think these patients need to be tested again for HER2-positivity. I think we can assume since these patients did not get any anti-HER2 therapy, that they'll probably be HER2-positive and can be treated with anti-HER2 therapy.

Dr. Pant: And you're so right, Amit. That's exactly right that, in GEA, it's more nuanced because they normally get something like trastuzumab frontline, whereas in BTC they're not getting a HER2-targeted therapy frontline, so it's okay not to retest if they're HER2-amplified in the beginning.

One of the other questions was, in your clinical practice, which of the following sample types do you use to test for HER2-positivity in your patient with BTC and/or GEA? About 40% said ctDNA. About 65% said tumor tissue. About 16% said I do not test for HER2 status. You should be testing for HER2 status. So I'm going to like, you know, correct it right there and I'm not sure about – what was about 16%.

So first to kind of answer some of these questions is we should be testing all our GEA and BTC patients for HER2 status. That is very, very important. But Amit, what do you use normally in your practice? Tumor tissue, ctDNA, you know, pros and cons of each.

Dr. Mahipal: Sure. I mean I think ideal is tumor tissue. So we do need to get tumor tissue. I mean there's no doubt that ctDNA can miss HER2-positivity. And then tumor tissue has higher sensitivity, I would say.

If the ctDNA is positive, most likely tumor tissue would be positive. So that's positivity; however, there are many cases where tumor tissue is positive and ctDNA can be negative. So at least in the first-line or at least the first time of diagnosis, for sure, I would recommend doing tumor tissue testing. If you don't have enough tissue, I would even recommend repeating a biopsy. So just to make sure we're not missing any HER2-positivity, because that could have great impact on how we treat the disease and the long-term survival outcomes.

The question becomes especially in GEA, you know, these patients who were initially HER2-positive got treated with anti-HER2-directed therapy. And then now they're progressing. What do you do at that time? And I think again, I would advocate if you can do biopsies, if feasible, safe, I would advocate for repeating a tumor biopsy.

Obviously, and sometimes if that's not feasible, ctDNA could be used as a surrogate marker. But just do remember that if ctDNA is negative for HER2 amplification, that does not mean that the patient is not HER2-positive.

Dr. Pant: Yeah, and I completely agree with you, Amit, that I really go with the tumor testing because I think that's the most reliable as the gold standard of testing in these patients. But sometimes when it's not feasible, it's not in a place where the interventional radiologist can really say, I can do this safely, then we think about doing ctDNA testing.

But I completely agree with you that tumor tissue should be at the top of that list. And then if we cannot do that safely for whatever reason, then ctDNA comes into play.

Dr. Mahipal: Now we're going to talk about a briefcase for a patient with biliary tract cancer. So 65-year-old gentleman who was diagnosed with metastatic gallbladder adenocarcinoma. He had a 30 pack year of smoking history, had stopped smoking about 10 years ago, had other comorbidities, including hypertension and diabetes. He also has a history of interstitial lung disease or pneumonitis, and required treatment with steroids. So patient was diagnosed about seven months ago, was on first-line treatment, and unfortunately now has disease progression and was found to have several new lesions in the peritoneum.

Patient has excellent performance status with ECOG performance status of one and all his labs are within normal limits.

Shubham, in this patient history, what are the characteristics that really help you make the next treatment decision for this patient?

Dr. Pant: I think there are a number of things. First of all, I'm going to look at the next-gen sequencing, like, what is the molecular target that I can utilize for this patient. That's very important. In that, I'm going to look for FGFR fusion. I'm going to look for IDH1 mutation, and I'm going to look for HER2 amplification. I think those things are very important.

The most important is how does the patient look? What's the performance status? I know you said performance status was one, but should the patient have had a performance status of three – That's very important to know because that would really guide our further therapy, should we continue to treat this advanced patient, or should we think about things like palliative care options for this patient essentially.

But this patient seemed to have a good ECOG of one. So I think I would go towards the next-generation sequencing in this patient trying to see if I can really give them a molecular targeted therapy at this stage.

Dr. Mahipal: Talking about NGS, like when do you do the NGS testing? Do you do at the time of diagnosis or after they're progressing in the first-line? What are your thoughts on that, and when should we get those results?

Dr. Pant: I think we should do it as soon as we see the patient in the front line. And there's a reason for that. Sometimes folks are like, “Hey, the – there are no approved drugs in the frontline setting, so why don't I do it in the second-line?” But what we have to understand is, let's say you have a patient, and you're treating the patient with chemoimmunotherapy and they progress. But sometimes the progression is fairly rapid. Then you're biopsying, then you're waiting for another month for it to come back. And then you might miss a clinical trial for the patient.

So if you have that NGS right there, they might have a KRAS mutation. You put them on a RAS-directed trial, or they could have, you know, an FGFR and they could go an FGFR trial. I know they’re approved agents, but there are trials also are out there. So I think it's very important in the decision-making that you need those results at that time for the patient to really make game-time treatment decision on this patient at that time.

If you wait for another month, you're getting a biopsy and that's another two weeks to get a biopsy, you know, call my favorite interventional radiologist to expedite that biopsy. Who knows, by that time the patients are on blood thinners and then further complicates matters. And then, you know, you're kind of delaying things, waiting for it. Maybe there's a clinical trial that might not be able to get on a clinical trial.

So I want my information upfront. I want it when the patient is there. Now what do I normally do? And we've discussed that before. I'm a big proponent of obviously tumor tissue for getting that whole next-gen sequencing, for getting that RNA sequencing, for that FGFR fusion, trying to find other targets that we might not have approvals for, but we might have clinical trials for. But if I'm not able to get a tumor tissue safely, then I go with ctDNA analysis, but I really try to go with the tumor tissue.

And so I think it's important to have that information available. And if we cannot do it, that's different. You know, sometimes we just cannot get the tumor tissue and we do the ctDNA and nothing shows up. So I wait for something new to metastasize and if I can biopsy at that time. But I'm always looking for lesions to biopsy if I can do it safely.

Dr. Mahipal: Great. Yeah. I mean, stressing the importance of tumor tissue biopsies for NGSs, you know, cannot be stressed enough, I would say.

So something we have adopted in our practice is actually when we have seen the patient first time, we would do both tumor tissue as well as ctDNA at the same time. So again, just to expedite as, you know, Shubham, you said like there are a lot of trials that are out there. It's really important to know those results. But again, the tumor tissue remains the gold standard.

We talked about the different biomarkers. And let's assume that this patient has HER2 IHC 3+ and did not find actionable targetable alteration, although that term keeps on changing as we get more and more therapies, but negative for like FGFR fusion or IDH1 or KRAS. What would be your next line of therapy in that case?

Dr. Pant: If the patient is IHC HER2 3+, we have two different options for the patient. We have trastuzumab deruxtecan that is approved, also zanidatamab which is a very unique kind of a drug. It's a biparatopic bispecific. So what that means is that it binds to two areas on the HER2 protein. It's on extracellular domain II and IV essentially, so binds it in two areas. And that leads to certain efficiencies of the drug.

But the trial which got this approved was a trial called HERIZON-BTC-01. And this is a unique trial. So the other – other drugs which have been approved or are part of the NCCN guidelines were part of a basket trial. That means it was trying different malignancies. So it could have been biliary tract cancer. It could have been ovarian cancer, some other cancers.

However, the HERIZON-BTC-01 was a biliary tract cancer-only trial, and that's important. It was a global trial. The efficacy analysis was done in about 80 patients who were HER2-amplified. And this was defined as HER2 IHC 3+ or a HER2 IHC 2+ and ISH positive, that means in-situ hybridization positive.

The maximum benefit was seen in the IHC 3+ patients. And the patients who were IHC 3+, the overall response rate for these patients was 52%, with a disease control rate of 79%. Not only that, the patients who got a response, it's important also to have a good duration of response. That means they're sometimes, as you know, in our trials or in when we're treating patients in real life, the patient can get a good response with their first scan, but they can be progressing with the next scan.

So though they've had a “partial response”, it might not be clinically beneficial for the patient because they could not hold that response for longer or the drug unfortunately could not hold that response for longer. But the duration of response, that means the patients who were responding, how long were they responding for, the median was about 14.9 months, which I think is very clinically relevant for these patients.

The progression-free survival in these patients was about 7.2 months. So important data and exciting data for our patients and which led to the approval of this therapy.

Dr. Mahipal: So just to follow-up on this patient, as you clearly stated that the patient would be a candidate for zanidatamab and patient did receive zanidatamab. Do we need to premedicate before giving zanidatamab infusion, what are your thoughts on that and the reason for that?

Dr. Pant: Great question, Amit. So it's actually in the package insert. To treat patients with zanidatamab, look in the package insert.

What happened was in the phase I setting, there was an increased risk of infusion reactions. Majority were, early on, grade 1 or 2. In the clinical trial, it is part of the trial that they received premedication before zanidatamab. So acetaminophen, diphenhydramine, hydrocortisone 30 to 60 minutes before administration of zanidatamab. And that's part of the package insert.

So yes, I would encourage folks to premedicate before zanidatamab, make it their standard of care or their SOP when they're giving zanidatamab.

Dr. Mahipal: Yeah, I think most of us use some sort of EMR system and it's automatically these premedication are included in that system.

Dr. Pant: Things thankfully have been made easier for us in some ways. Somewhere it’s harder. Somewhere it’s easier.

Dr. Mahipal: Yes.

So, as I mentioned, you know, this patient was started on zanidatamab. You know, about a month into treatment, this patient gives a like frantic call that he's having a lot of bowel movements. He had eight episodes a day of diarrhea. Is that a common occurrence or common adverse event of zanidatamab and how would you manage it?

Dr. Pant: Yeah, it's one of the most common adverse events of zanidatamab. Most folks don't get this much diarrhea. They get less diarrhea.Now you have to separate them out – becausegastroesophageal adenocarcinoma that we'll talk about later – in that it's with chemotherapy. So you have to give prophylaxis.

But if you're giving single-agent zanidatamab for biliary tract cancer, you really don't have to give prophylaxis. However, I talk to the patients, when I talk to them, I say, think about it like irinotecan. When we're giving irinotecan regimens, we talk to the patient, we say, “Hey, here's some Imodium. It's over-the-counter. Keep it with you. First sign of diarrhea, you take two pills of Imodium, and you take two every two hours till the maximum of Imodium, which is you know, about 16 milligrams.” So you kind of do follow-up with Imodium.

I tell the patient to call us immediately. Stay hydrated. You might have to add on a second agent called Lomotil sometimes, which is a prescription drug. But honestly, I've seen it well managed. I had one patient who got a decent amount of diarrhea with 20 milligram per kilogram. So you can dose reduce them to 15 milligram per kilogram which is a lower dose of this drug and the patient did well after that.

So there is diarrhea, but it's very manageable with this drug.

Dr. Mahipal: Yeah, I think it's important to know about this unique toxicity of some of these new or novel agents that we use and manage them appropriately, and providing that patient education upfront could help a lot.

Dr. Mahipal: Can you also provide a brief overview about efficacy from the survival perspective? I know you talked about response rates and duration of response, which was amazing in the HERIZON trial with over 50% response rate and duration of response over 14 months. And also talk about the most common treatment-related AEs apart from diarrhea?

Dr. Pant: Yeah. We've discussed the duration of response and the progression-free survival. In this trial for IHC 3+, the patients had a median overall survival of 18.1 months. You and I treat a lot of biliary tract cancer patients. This is significantly higher than you would think that you would get with chemotherapy because these patients have been pre-treated with some kind of therapy. These are not treatment-naive patients. So that's very encouraging.

Essentially, the main side effect as we talked about was diarrhea and infusion-related reactions. But infusion-related reactions can be mitigated with pre-medications. Rarely patients can get ejection fraction decrease. Wehave an echo or MUGA scan that we normally would do with any other HER2-targeted therapy.

And some patients – small percentage can get nausea and vomiting, but they are mostly grade 1 and 2.

Dr. Mahipal: Thank you, Shubham, for that overview.

Dr. Pant: Amit, I'm going to talk about the second briefcase study. Approximately five years ago, a 44-year-old man of African descent was diagnosed with chronic heartburn. Lab tests, endoscopy, and initial biopsy of the ulcer failed to reveal presence of malignant cells. For several years, heartburn was treated successfully, kept under control, and then the patient now presents with stage IV gastroesophageal adenocarcinoma with lymph node and liver involvement unfortunately. The patient still has a good ECOG performance status of one, no cardiac dysfunction, and has an echogram ejection fraction of 60%.

So, Amit, given the patient's history, which of the characteristics are important to make the next best decision for this patient?

Dr. Mahipal: Sure. Looks like he’s a young patient who is very healthy with an excellent performance status, no real comorbidities. So, he would be an excellent candidate to receive systemic therapy.

I think it was important to talk about the heart functions like EF of 60% is in the normal range. So that will not restrict us from giving therapies that could potentially have adverse event of cardiac function.

Dr. Pant: So what would you recommend as a next best treatment approach for this patient? And why would you do that?

Dr. Mahipal: The treatment for gastroesophageal cancers has changed a lot. Now before we do the first-line treatment, we need to know the biomarkers. I mean this is something new to GI cancers, I would say, in general, where initially, we'll just do some sort of first-line treatment and then based on the biomarkers, we'll decide on the second-line therapy.

For gastroesophageal cancer, this has changed totally. We need to know about some of these biomarkers before we can decide what the best first-line therapy would be. And these could include different immunohistochemistry markers, include microsatellite status, HER2, PD-L1, and now recently, claudin 18.2 as well.

So we need to know those biomarkers at least to know how we select the first-line treatment options.

Dr. Pant: You're right, Amit. Early testing is very important, especially in patients with advanced GEA because that can change the way you treat these patients depending on all the important biomarkers you talked about.

So Amit, for this patient, what would be the first-line optimal therapy?

Dr. Mahipal: This patient underwent biomarker testing so microsatellite stable, is HER2 3+, PD-L1-positive and negative for claudin 18.2. So, a couple of important biomarkers, both HER2 as well as PD-L1 are positive.

Based on the KEYNOTE-811 trial, this patient would be excellent candidate to receive trastuzumab plus FOLFOX plus pembrolizumab. So almost like what we call triplet therapy. So, you have chemotherapy as your base. And then you're adding pembrolizumab as an anti-PD-1 therapy and anti-HER2 therapy - trastuzumab. So FOLFOX plus pembrolizumab plus trastuzumab.

Dr. Pant: Could you talk about why you would treat the way you're treating?

Dr. Mahipal: Sure. Almost 15 years ago, there was a ToGA trial that was presented which transformed how we treat HER2-positive gastroesophageal cancers. In the ToGA trial, they randomized patients into chemotherapy or chemotherapy plus trastuzumab for patients who have HER2-positive advanced cancer as first-line treatment options.

That trial showed median survival improvement from 11 months with just chemotherapy alone to 13.8 months with addition of trastuzumab to chemotherapy. The response rates also increased from 35% to 47%.

More recently, KEYNOTE-811 trial was presented, which showed benefit of chemotherapy plus pembrolizumab plus trastuzumab compared to trastuzumab plus chemotherapy, which was established as standard of care. And median survival actually improved from 16.8 months with chemotherapy plus trastuzumab to 20 months with triplet therapy of adding pembrolizumab plus trastuzumab plus chemotherapy. And the response rate was 72%.

So just to keep that in mind when we're treating these patients in the first-line that we expect that majority of the patients, like almost 72% of the patients, will have some sort of response if we are treating with this triplet regimen. This led to the FDA approval for this triplet therapy in 2025.

Dr. Pant: According to your recommendation, the patient did receive kind of the triplet therapy with the FOLFOX checkpoint inhibitor and trastuzumab. Patient achieved a partial response tolerating the treatment very well. However, unfortunately, nine months on treatment, experienced disease progression with increasing number of liver lesions.

ECOG PS is still one. It's excellent. Repeat biopsy, as we've talked about before, was done. A fresh tissue sample received an HER2 IHC of 3+, but no other actionable gene or protein alteration was detected.

At this time, Amit, what is the next best treatment for this patient?

Dr. Mahipal: Just a couple of things. This patient did undergo repeat biopsy and was found to be HER2-positive. This means that patient has persistent HER2-positivity.

We have a drug called trastuzumab deruxtecan, which is approved for patients who have progressed on kind of a regimen that this patient got, including anti-HER2 therapy and chemotherapy with gastroesophageal adenocarcinoma who progressed and they are still HER2-positive on the repeat biopsy.

Dr. Pant: Can you talk to us a little bit about DESTINY-Gastric01 trial?

Dr. Mahipal: Yeah. The DESTINY-Gastric01 trial, it was a randomized, phase II trial, which used trastuzumab deruxtecan for patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma, who had previously progressed on, you know, first-line treatment including trastuzumab.

These patients were randomized into T-DXd or trastuzumab deruxtecan or standard of care chemotherapy typically involving irinotecan or paclitaxel. And it showed improvement in the median survival from 8.9 months with the chemotherapy group to 12.5 months with T-DXd. And similarly, the median PFS was also improved from 3.5 months to 5.6 months with hazard ratio of 0.47.

So this led to FDA approval for T-DXd for patients with metastatic HER2-positive gastric cancer who had previously received first-line trastuzumab-based regimen and had progressed.

Dr. Pant: So in this patient, the decision was made to administer trastuzumab deruxtecan. Could you tell us about the adverse event of special interest that you need to counsel the patient and caregiver about?

Dr. Mahipal: So T-DXd or trastuzumab deruxtecan has a unique side effect of interstitial lung disease or pneumonitis. And that's something we should be really aware of. So any patient who develop shortness of breath, right away we need this patient to be evaluated, get a high-resolution CT. And if you think there's a sign of interstitial lung disease, immediately start treatment.

Typically, we do like steroids and there are guidelines of how to treat them. So like for grade 1, I will start like about 0.5 milligrams to one milligram per kg of prednisone or equivalent. And similarly for grade 2 or higher, we'll do one milligram per kilogram of prednisone or equivalent.

The steroid regimen is given a little bit longer. You start this therapy, you give it for at least two weeks. If the patient is improving, then do a slow taper over four to six weeks and you do taper every week. So this is not like a short-term steroid treatment but a little bit longer treatment.

The main thing about this is that we need to identify that early. You know, high-resolution CT can pick that up. And sometimes you just need a pulmonary input as well. You might have to rule out other causes of interstitial lung disease, including atypical infections. So may need recurrent like bronchoscopies, PFTs, etc. and primary groups can definitely help.

And depending on what kind of grade it was initially and how it resolved, like, so if it was like, say, grade 2, went down to grade 1, patient is now asymptomatic, you can still restart T-DXd. So you can still give it. You have to give it at a dose reduction, so at that point. So give it a first dose reduction depending on the what dose you started. So for gastric, the approved dose is 6.4 milligram per kg. And if that's the dose that you started, then you go to one dose reduction to 5.4 milligram per kilogram and so on.

Dr. Pant: Yeah. The main thing is for interstitial lung disease, one takeaway is that you've got to recognize it early. If you recognize it early, you've got to take the corrective actions.

Amit, can you tell us about other agents which are coming out for the treatment for HER2-amplified gastroesophageal adenocarcinoma?

Dr. Mahipal: Yeah. So the HER2-positive field is getting more and more exciting with the newer agents coming up. Similar to like BTC, we talked about the use of zanidatamab. There was a trial called HERIZON-GEA-01. And in this trial, they're testing again as a base is of trastuzumab plus chemotherapy and trying an experimental arm of zanidatamab plus chemotherapy with or without tislelizumab, which is an anti-PD-1 inhibitor.

So zanidatamab, as you mentioned, is an anti-HER2, biparatropic antibody and binding to two epitopes on HER2. So in this three-arm trial, they randomized almost 900 patients. One is trastuzumab plus chemotherapy. That's your kind of a base line arm. And then arm B was zanidatamab plus chemotherapy. And then we have a third arm where we're testing zanidatamab plus tislelizumab plus chemotherapy.

This trial had a dual endpoint of PFS and overall survival. And the median PFS was improved from 8.1 months with trastuzumab plus chemotherapy to 12.4 months with the triplet regimen of zanidatamab, tislelizumab plus chemotherapy. And the hazard ratio was 0.63.

Interestingly, the median PFS was also improved for zanidatamab plus chemotherapy compared to trastuzumab plus chemotherapy as well from 8.1 months to 12.4 months.

In terms of overall survival, we saw a significant benefit with the triplet regimen. The median survival improved to 26.4 months, with hazard ratio of 0.72. The data is still ongoing, so may have more update. Zanidatamab plus chemotherapy showed median survival of about 24.4 months.

Dr. Pant: Okay. Amit, in your clinical practice, what do you think are the persistent needs with appropriately sequencing HER2-directed therapy for patients withadvanced GEA and advanced BTC?

Dr. Mahipal: For patients with advanced GEA, the field is getting crowded.

The field is getting complicated where it's becoming very challenging to know what kind of HER2 therapy is approved for what cancers. We have diseases like breast cancer where a lot of anti-HER2 therapies are approved. But in gastroesophageal cancer, there are only few anti-HER2 therapies that are approved.

In the first-line as of today,it's trastuzumab plus chemotherapy plus pembrolizumab. And in the second-line, T-DXd. We just talked about HERIZON GEA data which showed that zanidatamab plus tislelizumab plus chemotherapy might be an intriguing option which could be available in future as well.

The biggest takeaway is do the HER2 testing, you know. When you have a patient, try to get the tissue and do the HER2 testing, and do not start the patient on the first-line treatment before testing these biomarkers, because really, that's how we will decide. Obviously, there are options for clinical trials as well.

And then second thing is once the patient has progressed on the first-line regimen, including trastuzumab or some sort of anti-HER2 therapy, I think we have to do a repeat HER2 testing, which would frequently require a repeat biopsy, because many of these patients can lose their HER2 amplification. So, if they were HER2-positive and you treated them with anti-HER2 therapy, they may no longer be HER2-positive. And in that case, they will not benefit from further anti-HER2-directed therapy.

Dr. Pant: It's very important, Amit. And same thing for BTC. If you look at it, essentially, you know, we should do the HER2 testing for the patients with biliary tract cancer. There are two good options available, zanidatamab and trastuzumab deruxtecan. We don't know how to sequence these. I think we'll come to know more as time progresses, as to how we can sequence these different options.

Sometimes what I do in my practice is the patients are coming off gemcitabine-cisplatin and a checkpoint inhibitor. And if they have a lot of fatigue or challenges with chemotherapy, then I think about zanidatamab just to give them a chemotherapy-free interval. But both agents are active in this disease. And it's good to have options to treat our patients.

Dr. Mahipal: Shubham, for talking about BTC. So the anti-HER2 therapies are currently approved in the second-line or later setting. Can you just talk briefly about some of the key ongoing trials? Andis there a thought of bringing that in the first-line setting?

Dr. Pant: Yeah, it's very important. Because about 40% of patients can drop off second-line. So let's say about 100 patients were treated with front-line therapy, only about 60 patients or 50 patients might be treated with second-line therapy. So we want to try to give the benefit to the patients in the front-line.

And we have two really exciting trials in the frontline setting, HERIZON-BTC-302, which is a global trial of zanidatamab with standard of care. Basically standard of care with or without zanidatamab. And we also have the DESTINY-BTC-01, in which T-DXd is being combined with rilve, which is a bispecific immune checkpoint inhibitor.

So there are different trials which are global phase III trials, which have moved these anti-HER2 therapies to the front line. We're really excited about patients being accrued to these trials and the data readout coming out in the years ahead.

So, Amit, what are you excited about in HER2-positive gastric or gastroesophageal adenocarcinoma?

Dr. Mahipal: We'll continue to see the HERIZON-GEA data from the follow-up. And secondly, if the FDA would approve these drugs and then we have more or better therapies available for these patients. So also good to see that we are pushing the boundary where median survival used to be about a year for these patients, and now we're almost at the two-year mark already or exceeding that mark.

The other thing is we are trying to bring these anti-HER2 therapy in earlier settings. We already have it approved in the first-line and second-line advanced setting, but there are trials going on trying to test anti-HER2 therapy in resectable HER2-positive patients. And there it could make a bigger difference if we can improve the cure rates; it could have much bigger impact.

Dr. Pant: All right. What are your final thoughts?

Dr. Mahipal: Testing, testing, testing. That's the most important thing. We need to test the tissue every time. So before the first-line, and if you have treated the patient with anti-HER2 therapies prior to the next line of therapy. So we have drugs that are approved in the first-line as well as in the second-line.

Currently, we have trastuzumab-based chemotherapy in the first-line setting. And in the second-line setting we have T-DXd. But as I mentioned, the HERIZON-GEA data, which is very exciting, which could have zanidatamab plus chemotherapy with or without anti-PD-1 blockade in the first-line setting. So exciting times ahead.

So, Shubham, do you want to talk about BTC and how HER2-positive BTC is being shaped up?

Dr. Pant: Yes, testing, testing, testing.Do the NGS, that's important. Tissue testing is important. I think we have a lot of exciting options for our patients with targeted therapy in BTC.

I like to call BTC the lung cancer of GI malignancies. We have a number of targets in BTC, but we will not be able to give any of those drugs to patients if we don't test them. So that's very important.

And please do look for clinical trials for your patients in the frontline setting, because there are a lot of exciting molecularly targeted trials which are out there with zanidatamab or with trastuzumab deruxtecan in the frontline setting for HER2-amplified biliary tract cancer.

So with that, I'm going to thank our audience for learning about HER2-amplified biliary tract cancer and gastroesophageal cancer. Thank you so much.

Dr. Mahipal: Yeah. Thank you.