Dr. Shubham Pant (MD Anderson Cancer Center): Welcome to our podcast on HER2+ Gastroesophageal Adenocarcinoma and Biliary Tract Cancer. I am Dr. Shubham Pant. I am a Professor of GI Medical Oncology at the MD Anderson Cancer Center in Houston, Texas. With me today is Amit.

Dr. Amit Mahipal (Case Western Reserve University): Hi. I am Dr. Amit Mahipal. I am a Professor of Oncology at Case Western Reserve University.

Dr. Pant: On our agenda for today, we are going to:

• Provide a brief overview of BTC and GEA. That is biliary tract cancer and gastroesophageal adenocarcinoma;
• Talk about approved HER2-directed therapies for BTC and GEA and their mechanisms of action;
• Talk about efficacy and toxicities of approved agents, and more importantly, optimal treatment strategies;
• Discuss the key ongoing trials of HER2-directed therapies in BTC and GEA; and
• Finally, end with challenges faced by healthcare professionals in the management of patients with BTC and/or GEA.

Discussion

Amit, I want to kick off this activity by asking you the general question. Which specific biliary tract cancer and gastroesophageal adenocarcinoma are commonly associated with HER2 positivity? That means is there a subtype which has high HER2 expression in BTC or GEA?

Dr. Mahipal: Yes. For the BTC or biliary tract cancer, we typically divide them into intrahepatic cholangiocarcinoma, hilar, and then extrahepatic cholangiocarcinoma and gallbladder cancer.

The highest rate of HER2 expression tends to be in gallbladder cancer and extrahepatic cholangiocarcinoma, with rates approximately around 20% or so. Gallbladder can be as high as even 30%, depending on what studies you are looking at, as compared to intrahepatic cholangiocarcinoma, where the rates are actually pretty low, probably less than 5%.

In the GE junction or gastroesophageal cancer, it is not entirely clear, but GE junction cancer tend to have a little bit higher rates. There is some differences between the intestinal and diffuse type in terms of the HER2 expression. But again we will recommend testing for all of these subtypes.

Dr. Pant: What you are telling me is that all patients with gastroesophageal adenocarcinoma and biliary tract cancer should be HER2 tested regardless of where the origin is, if it is gallbladder intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma because it can happen anywhere, and similar case with gastroesophageal adenocarcinoma. Is that correct?

Dr. Mahipal: Absolutely correct. I just want to again clarify, even though there are differential rates based on the different subtypes, especially like bile duct cancer, we would still recommend testing for everyone because even if it is a low rate of expression, if we can find it, I mean, those patients can benefit a lot from HER2-directed therapies that we will be talking about in a few minutes.

Dr. Pant: The first thing is, if you do not test, you will not find. The second thing is no patient left behind, right? That is very important. Tell me, Amit, and this is a very clinical question, because we are not pathologists, we love to play pathologists as oncologists sometimes and radiologists. But in clinical practice, how do you assess HER2 positivity in your patients with biliary tract cancer and gastroesophageal adenocarcinoma? What are the nuances of this? Because I know it is like an onion, right? There are multiple layers to this.

Dr. Mahipal: Yes. That is becoming a tougher and tougher question like how do you test for HER2? What methodology do you use? Traditionally, HER2 testing has been done in breast cancer, and a lot of these data came from breast cancer and we try to apply to different GI cancers. What we have found is the HER2 expression in breast is very different than HER2 expression in GI. Pathologists have different IHC scoring for gastrointestinal cancer, especially talking about GEA and BTC compared to HER2 expression testing by IHC even in breast cancer.

I think standard of care, if you want to test for HER2-positive should be immunohistochemistry. At least for gastric cancer or gastroesophageal cancer, what we recommend is you test by IHC first. If it is 3+, it is positive. It is zero or one, it is negative. If it is 2+, then you test like a reflex test or FISH. If FISH shows overamplification, then patient is considered HER2-positive.

For biliary tract cancer, you can definitely use the same approach, but the indication for treatment is for patients who are HER2 3+ by IHC. So restrict to immunohistochemistry.

Again, for both cancers, HER2 testing should be done by IHC as a first step, and if they are 2+, then could be consider FISH. Then there are other tools like NGS. You can look at mRNA amplifications. They may correlate very well with IHC or protein overexpression. But just again to be clear, some of the drugs are not approved just based on HER2 mRNA amplification. They are mainly approved based on IHC testing and FISH testing, if IHC is 2+.

Dr. Pant: If I had to drill this down, Amit, what you are saying is you need to test by immunohistochemistry. When you look at the report of patients with biliary tract cancer comes in or gastroesophageal adenocarcinoma, send that test off for IHC, quick cheap test to do in a way. But what about next-gen sequencing, Amit, you talked a little bit about. Because those are two big tests we send like. A patient goes and they have next-gen sequencing HER2 amplification. What do you do with that?

Dr. Mahipal: Correct. I mean, again, we will talk about the treatment options. For right now at least the FDA approval is only based on the protein overexpression by immunohistochemistry and/or FISH testing, and not based on HER2 overamplification.

What we have found is patients who are HER2 overamplified, they are very, very highly correlated with protein overexpression as well. Unfortunately, it is not 100%, but very highly correlated. If you do have a patient with HER2 amplification, if you found by NGS, if your IHC has not been done, I would strongly recommend to try to do it. If you need extra tissue, go for a biopsy to get extra tissue to do it. But I think that is the patient you should strongly consider for HER2-directed therapy.

Dr. Pant: What about everybody's favorite kid, as we say, ctDNA, circulating tumor DNA. When do you bring that into the mix?

Dr. Mahipal: Yes. At least for initial testing, I think we should not rely on ctDNA, especially for RNA amplification. They can pick up some DNA amplification. But many times if ctDNA would miss HER2 positivity. I think just to rely on ctDNA or circulating DNA positivity as an initial step is not a good practice. I think we will definitely want to have a tumor tissue testing. Make sure do it again, as I said, by IHC, FISH and other methodology just to make sure they are positive or negative. But circulating DNA as an initial test is not a great test.

However, sometimes it can help in some monitoring of patients who are on HER2-directed therapies where we can talk about later on, but at least initial testing, we would not recommend doing circulating DNA for HER2 testing.

Dr. Pant: Yes, I agree with you. I think though some folks really are in the ctDNA camp, but I am with you there that tumor tissue is what we need to go for if we really need to. What about retesting, Amit, in gastroesophageal adenocarcinoma? Or let us say, in biliary tract cancer, somebody got gemcitabine-cisplatin-durvalumab frontline or gemcitabine-cisplatin-pembrolizumab frontline. Would you test them for HER2 again, and you had the initial biopsy which is HER2 amplified.

What about gastroesophageal adenocarcinoma? Somebody who had HER2-directed therapy, let us say, as trastuzumab frontline. So how do you distinguish between the two?

Dr. Mahipal: There is some interesting data that is coming out that shows patients who are HER2-positive and went on to HER2 therapy, and then they progress, should we consider another biopsy at that time to see if they still retain that HER2 positivity before considering second-line HER2-directed therapy?

I think in the biliary tract cancer, where we are just giving chemoimmunotherapy and not HER2-directed therapy as a first-line. Even if they are positive at baseline, I am not sure at progression. Their HER2 positivity would change since they did not receive HER2-directed therapies. But there are people in the camp who would really strongly advocate, at least for the patient with gastroesophageal cancer who have received HER2-directed therapy and have progressed to retest them, make sure they are still HER2-positive. If that is the case, then go for the second-line therapy.

Again, we have not done this as prospective trials, but I think it is a good idea, good practice just to make sure they have not lost the HER2 positivity.

Dr. Pant: What you are saying is there is a difference. In gastroesophageal adenocarcinoma, if you have had previous HER2-directed therapy like trastuzumab, maybe you do want to retest them before you expose them to trastuzumab deruxtecan, because again these therapies are not without toxicities.

However, in biliary tract cancer if they are not, the frontline is gemcitabine-cisplatin with a checkpoint inhibitor, you really do not think the HER2 status would have been changed, just because they did not get a prior HER2 therapy and you really potentially do not need to retest them. You can just take the first test.

Dr. Mahipal: Shubham, now I am going to ask a few questions about HER2-directed therapies in general. What are the FDA-approved HER2-directed therapies for patients with biliary tract cancers?

Dr. Pant: Yes. Exciting times. If you had asked me this question, like two years ago, I would have said nothing. However, things have changed dramatically. The whole landscape is changing.

There are two drugs out there, Amit, which have gained accelerated approval for second-line after frontline basically. One is a drug called trastuzumab deruxtecan, which we know for a long time because of breast cancer. Our breast cancer colleagues started with HER2+. Then they went to HER2-low and went to HER2-ultralow. How low can you go?

That is just breast cancer. But for us, again, as you said, the approval was for HER2 3+ IHC. This was based on a trial called DESTINY-PanTumor02, in which essentially patients with different HER2 amplifications, it was not even overexpression, it was not even biliary tract cancer. It could be pancreatic cancer, ovarian cancer or some other gynecological cancers were treated with trastuzumab deruxtecan as a basket trial.

The response rate in HER2 3+ was about 56% in these patients. That was approval for trastuzumab deruxtecan.

The second one is what I call the new kid on the block is zanidatamab. This is a very interesting agent and we will talk about the mechanism of action a little bit later. But essentially this has also been approved for HER2 3+, where it showed a response rate of 52% in these patients.

Now, the interesting thing about zanidatamab was most of the other HER2 trials have been done as a basket trial. We have others like trastuzumab-pertuzumab, which is part of the NCCN guidelines. We have tucatinib-trastuzumab which is also part of the NCCN guidelines. And trastuzumab deruxtecan, which got its approval based on a basket trial.

The unique thing about the zanidatamab trial, which is called HERIZON-BTC-01, was that this was an exclusive trial done exclusively in patients with biliary tract cancer. It is a global trial. 80 patients were accrued. This drug was given IV once every two weeks, and patients got scans every two months. Like I said, the response rate in the HER2 3+ was about 52%.

More interestingly, and exciting for us as clinicians was the duration of response. That means the patients got a response. Their duration response of 14.9 months, which I think is fairly remarkable in patients with refractory disease for frontline therapy. The median overall survival for HER2 3+ patients was 18.1 months, which you know, treating biliary tract cancer, that is fairly remarkable in this setting.

Excited to have not one, but two drugs approved in this kind of rare setting for patients.

Dr. Mahipal: Thank you, Shubham. Just to recap, so there are two drugs that are now approved for HER2-positive bile duct cancer. One is trastuzumab deruxtecan. Second is zanidatamab, with zanidatamab trial being really studied in just the bile duct cancer population and T-DXd or trastuzumab deruxtecan doing a more of a basket trial.

What line of therapy is it approved? Is it like frontline or second-line or later?

Dr. Pant: It is not frontline. This is after frontline therapy. Technically, you could do a second or third-line. It is after frontline therapy that these therapies are approved.

Dr. Mahipal: Okay. As long as patients have progressed or not tolerating one line of therapy, patients can receive HER2-directed therapies. Based on this response rate or excellent response rate, we will probably recommend going for these therapies more in the second-line rather than third-line, because you do not want to waste the opportunity if the patient has targeted therapy available for these patients, and we typically do not see such a high response rates with bile duct cancer, definitely not in second-line or later.

Dr. Pant: I would definitely agree with that. You are right. Absolutely.

Dr. Mahipal: Tell me a little bit about this mechanism of action of zanidatamab? How is that different from trastuzumab or T-DXd? I mean, we hear all these anti-HER2 drugs and sometimes hard to wrap our minds around, like how are they different.

Dr. Pant: I will start with trastuzumab deruxtecan. Folks know about the mechanism of action. It is an antibody drug conjugate. That means it is akin to a smart bomb. It is like a heat seeking missile. The target is HER2, which blinks brightly. It just attaches and releases the payload inside it. That is your trastuzumab deruxtecan, more like a guided missile.

Then you have zanidatamab, which is a very interesting construct. It is a bispecific, biparatopic drug. What do I mean by that? This does not bind to CD3. It really does not have things like CRS or cytokine release syndrome. But this binds to two domains on HER2 called ECD2 and ECD4. That is extracellular domain two and extracellular domain four.

Interestingly, these are domains that trastuzumab pertuzumab bind to. Because it is two drugs in one, it actually has a better impact, better receptor internalization. It has certain ADCC, so certain ways that it acts, which could be more beneficial or efficacious for the patients than just using single agents of two drugs. It is almost two drugs in one. But it leads to more synergism and more potency having those two drugs in one.

It is called a bispecific, biparatopic. Not to be confused with other bispecific that are approved for lymphoma, let us say, where this does not cause the CRS because it just binds to these two domains on HER2.

Dr. Mahipal: Do you think that is why zanidatamab - not cross-trial comparisons - seems to have more efficacy both in bile duct cancer and GE junction cancer or gastroesophageal adenocarcinoma as single-agent compared to, say, trastuzumab?

Dr. Pant: Yes, I think so. I have treated before all these drugs came by approvals, trastuzumab deruxtecan and zanidatamab. We treated patients with biliary tract cancer with trastuzumab, combo of trastuzumab pertuzumab. I did see some responses in that, but not to the level that I am actually seeing with these two drugs now.

Dr. Mahipal: We’ve talked about efficacy, talked about some of the mechanism of action. Let us talk a little bit about like adverse events. What kind of side effects do we see? Let us start with zanidatamab. What’s the most common adverse events that we tend to see with this in your clinical practice? I know you were involved in the trials as well. Just give your thoughts on that.

Dr. Pant: Yes. Folks know a lot about T-DXd because of breast cancer, other cancers. Folks have used it a lot. Zanidatamab, interestingly, the first approval was in biliary tract cancer, so folks have not used it a lot. I have had a number of patients with it, as you know, on the clinical trial, and now I have actually commercially treated a few patients with it, since it being available.

Main side effect that you need to look out for zanidatamab is diarrhea. What you do is you talk to your patients, just like I would talk about giving irinotecan. I educate them about it. I say here is Imodium, keep it next to you. Two pills with every loose stool, two pills every two hours. We have this what we talk about with irinotecan-related diarrhea. You hydrate yourself.

If it is not happening, then we can give Lomotil. There is a dose adjustment for zanidatamab. It starts at 20 milligram per kilogram. If you cannot tolerate it, you can go down to 15 milligram per kilogram. So it depends. But normally this is very well tolerated.

The other thing with zanidatamab that you have to keep in mind is that patients need premedication, so it can have infusion-related reactions. All patients do need premedication, with Benadryl and with a steroid and H2 blocker maybe. It needs a premedication, because it can cause infusion reactions, but otherwise, honestly, it is fairly well tolerated.

Trastuzumab deruxtecan. Again, the common side effect is nausea, anemia. It is like giving chemotherapy, I think, for a biliary tract cancer patients. With my biliary tract cancer patients, I do see them get nausea, fatigue, anemia, neutropenia. Classic chemotherapy side effects.

Though I said it was a targeted therapy, it does have chemotherapy-related side effects. Obviously, though rare but deadly, which can be associated with high morbidity is your interstitial lung disease. Recognize that early. Pneumonitis. Make sure you hold the drug. Treat it early. That is very, very important. Even if you see some little changes in the CT scan of the chest.

Normally, what I say is I talk to my patients, I say, “Hey, when you walk, do you get more winded? Are you walking up the steps, stairs and you cannot walk anymore?” Little clues which would give me some idea about if they are getting this toxicity.

Again, it is reversible. It is easily treatable. But we just need to be aware of the toxicity. They are different drugs as far as toxicity are concerned, definitely.

Dr. Mahipal: Yes. Definitely it seems like very different side effects. But I think just for a recap, one or two key side effects for zanidatamab will be primarily diarrhea and maybe some infusion-related reactions. Then for T-DXd will be cytopenia, fatigue, and more importantly, just to keep a watch out for pneumonitis or interstitial lung disease.

Dr. Pant: That is right, Amit. We have talked about biliary tract cancers. Let us talk about gastroesophageal adenocarcinoma. Could you give me a little bit of treatment landscape for HER2-directed therapies for patients with GEA?

Dr. Mahipal: Yes. HER2-directed therapies for GEJ actually has a little bit more and has evolved over years. One of the first trials, the ToGA trial, which led to approval of trastuzumab in combination with chemotherapy was in 2010. Then we have another combination of chemotherapy plus pembrolizumab, and chemotherapy plus trastuzumab as well in the first-line setting.

Then in the second-line setting or later we have T-DXd or trastuzumab deruxtecan. For GEJ junction cancer, we have approval in the second-line or later setting for patients who have progressed on trastuzumab-based combination chemotherapy.

Dr. Pant: Okay. Tell me about what HER2 expression levels they are approved for?

Dr. Mahipal: As we just talked about, so HER2 expression for gastroesophageal cancer, we require it to be IHC positive, so IHC 3+. In case if they are IHC 2+, if they are FISH positive, they can receive HER2-directed therapies or they are eligible to receive for HER2-directed therapy. Either HER2 3+ by IHC or 2+ with FISH positive.

Dr. Pant: In your clinical practice, what has been your experience with trastuzumab deruxtecan, like AEs? Again, what do you see in your clinical practice?

Dr. Mahipal: Just talking about trastuzumab. We use it again in combination with chemotherapy or chemotherapy plus immunotherapy if their CPS score is one or higher. Most of the side effects are not driven by trastuzumab. I would say that most of the side effects are actually driven by chemotherapy, and that we have seen with a lot of chemotherapy combinations.

Trastuzumab does affect the heart. That is something we are always cautious about and we have to do either echocardiogram or MUGA on a regular basis just to make sure your ejection fraction is not decreasing. If it is, then get a cardiologist right away and you may have to interrupt the treatment.

We talked about T-DXd. Shubham, as you mentioned, it is the same side effects as a chemo-like side effects, like cytopenias, fatigue, nausea, and then just to watch out for interstitial lung disease. At least in the trial with GE junction cancer, we see about 10% rate of interstitial lung disease. So it is not that infrequent. Just to keep an eye for those. Obviously, if someone develops pneumonitis that can even lead to a fatal event in rare cases. I think early recognition and treatment with steroids holding treatment can really help and prevent pneumonitis in these patients.

Dr. Pant: So, kind of similar side effects and everything what you see, T-DXd more like chemo. Trastuzumab is in combination with chemo. But overall we have used it for a long time.

Amit, coming to what we have talked about the new kid on the block, right? Zanidatamab. Now it has got an approval in BTC. What do you think about its chances in gastroesophageal adenocarcinoma? Where are we? What trial is going on right now?

Dr. Mahipal: As you mentioned, right, zanidatamab has very high single agent activity, which we typically do not see just with single anti-HER2 antibody like trastuzumab. We saw that great activity in bile duct cancer. Now they are trying to test in other HER2-positive cancers like GEJ cancers.

They are looking at zanidatamab in combination with chemotherapy with or without anti-PD-1 inhibitor, like tislelizumab, for patients who are HER2-positive with advanced gastroesophageal adenocarcinoma. It is a first-line trial, randomized phase III trial looking at addition of zanidatamab to chemotherapy plus/minus tislelizumab.

Dr. Pant: Hopefully we will potentially have more options for our patients with HER2 overexpressed gastroesophageal adenocarcinoma. But we have to wait for the readout of this trial, which we hope should be coming soon.

Dr. Mahipal: Shubham, what are the challenges faced by healthcare professionals in the management of patients with both biliary tract cancer and gastroesophageal adenocarcinoma.

I mean, both these cancers tend to be somewhat on the rarer side. There is some unique management for these cancers, especially now we are talking about HER2-directed therapies in particular. What is the challenge for the HER2 testing for your patients?

Dr. Pant: Tissue is an issue, right? The three most challenging words oncologists can get from pathologists is QNS, quantity not sufficient. It is really challenging. Because again, you do test for multiple things. There is some tissue goes for next-gen sequencing. Then you are trying to do IHC on it.

For us at MD Anderson, we really try hard. Like if patient has had a biopsy and we cannot do the NGS because it is not sufficient, if there is something which can be biopsied and is appropriate, then we definitely try to go for it and try to get some tissue. If not available, then I kind of reflex to ctDNA, but something so that I know I have tried to get some kind of sequencing for these patients because like I said before, if you do not look, you will not find.

I really try to do all I can. Because the thing is, Amit, folks may say, “Oh, let us do it frontline. We are going to treat in BTC with gemcitabine-cisplatin-durvalumab and there is not enough tissue. And when they relapse, we will do the biopsy.”

In my opinion, what happens is like by the time the patient progresses and then you are doing the biopsy and then waiting to start the second-line therapy or some clinical trial. I think really NGS testing and biliary tract cancer has moved to the forefront, I think because it tells us options for patients, eg, clinical trials. As we know, there is a phase III frontline trial going on with zanidatamab in biliary tract cancer, so can help me identify patients for that.

I try to get it as early as possible. For gastroesophageal adenocarcinoma, obviously you need to be checking for claudin expression, for HER2 expression, for PD-L1. Though I will tell you I am always confused about like the PD-L1 percentage, right? Is 1% good? Is the 10% good? Claudin, is it a 2+ staining, 20% staining?

I think in GEA, more than anything, pathologists keep us on our toes. But I am hoping they could just come up with an easy HER2 1+, 2+, 3+. 3+ is great. 1+ is negative. We do not have to peel that onion as I say. But I try to do it as early as possible for testing.

Dr. Mahipal: What would you do? You mentioned like quantity not sufficient. And you have a patient like this is something we commonly face. Do you go ahead to do another biopsy before you start first-line treatment, or do you try to do during the first-line treatment? Because I totally agree. Once they progress on first-line and then you are trying to do biopsy and then you are trying to do second-line therapy. Sometimes you don’t want to wait too long when the patient is progressing on the first-line itself, right?

How do you decide when to treat the patient with the first-line therapy or just wait for another biopsy and doing those HER2 or NGS testing on that before you actually initiate treatment?

Dr. Pant: Mostly, obviously for GEA, I want to get at least those biomarkers back because it can change the treatment that I am giving them to the frontline. For BTC, maybe less so because really we can use the target therapies in the second-line like FGFR, IDH1 and HER2. So more for GEA than for BTC.

I mean, if BTC, I do not get it and I think patients need to start therapy, I start them and then I try to get it sometime during the course honestly.

Dr. Mahipal: That makes sense. For GEA because we have approval in the first-line and it makes a huge difference obviously in the first-line setting. So it is really important to get biomarker testing. If you do not have enough tissue, just go for a repeat biopsy before you start first-line.

What you are saying for the BTC, at least you can start treatment. But regardless, you should try to get biopsy then as soon as possible, even if they have started in the first-line, do not wait for the patient to progress on the first-line therapy before doing repeat biopsy.

Dr. Pant: What do you think about insurance coverage issues? Maybe less of an issue for me, maybe more for you. But what do you think, in the community, any problems with testing?

Dr. Mahipal: I mean, these are FDA approved tests. Nowadays, at least for biomarker testing, there should not be any insurance coverage issues. If there is, I mean, we can always obviously appeal those issues. But in general, I think insurance coverage for HER2 testing or NGS testing for any patient with advanced cancer should not be an issue for these two cancers.

Dr. Mahipal: How do you keep up-to-date with this treatment guidelines and relevant literature in the field? It is so complex. As you were mentioning, the HER2-positivity in breast is so, so much different. Then even with BTC and GEA, there may be some nuanced differences. How do we keep up? What would you recommend for oncologists who might not see these patients that commonly, but still see them enough to make sure they get the best treatment?

Dr. Pant: That is a tough one, right? We are blessed, me and you, that we focus on a few tumor types, mostly GI cancers. So we are able to maybe drill down. Even with that, it is getting difficult, honestly. There is so much change in all the cancers, so it is still challenging. But I really feel for our community oncologists who could be seeing breast cancer, then a colon, then a lymphoma, then some other sarcoma or some other cancer.

It is very hard to keep up. What I would say is listen to podcasts like this, which is important. What we really do is just do the next-gen sequencing and then refer to NCCN.

You will be surprised. I have had a chat with a few community oncologists, even after the approval of T-DXd and zanidatamab in BTC, where they are like, “Oh, I am starting them on trastuzumab because that is all I have.” It is just about education. Just education, education, education, getting ahead of it. People like you and me having these chats and educating folks that they are approved therapies out there for HER2 amplified biliary tract cancer, because that is a very rare cancer.

Gastroesophageal adenocarcinoma still is a little bit more common, and HER2 has been tested there. Just because of the ToGA trial, trastuzumab has been around for a long time. I think that is so much of an issue, maybe retesting before T-DXd could be an issue, but BTC definitely, because it is so rare somebody might be seeing one in a year in their practice, right? Or maybe a couple in a year.

It is I think just about education, education, and more education on it.

Dr. Mahipal: You can certainly go to ASCO guidelines or NCCN guidelines. Again, it is so hard to keep up. These guidelines try to keep up to date as much as possible. These things are obviously presented at different conferences. I would again stress that in addition to NGS, we need to do HER2 testing for both these cancers. I would even argue for all GI cancers. But again our focus topic is both GEA as well as BTC.

Shubham, just talk a little bit about the sequencing of HER2-directed therapies. I guess we are not there yet in bile duct cancer, but what are your thoughts? Is that something coming up? Obviously, for GE junction we have more than one therapies available. There you could consider sequencing. But what are your thoughts on that?

Dr. Pant: For GEA, trastuzumab frontline is used. Then you can use trastuzumab deruxtecan in the second-line setting as far as approval is concerned.

For biliary tract cancers, again, after frontline, You could use trastuzumab deruxtecan or zanidatamab in the second-line setting. People ask me conference all the time, which one would you do first? Honestly, both are good therapies. Both have good efficacy. They look fairly similar. These are good therapies, so I would treat patients with this.

As you said before, Amit, it is important to get it early. So we are not waiting for third line setting, just these patients. We can get them on the second-line setting. The difference that I do feel is in the toxicity. I sometimes feel like continuing trastuzumab deruxtecan for patients with BTC, they get the nausea, fatigue, anemia, thrombocytopenia, and if they have come off six to eight months of gemcitabine-based chemotherapy with checkpoint inhibitor, then they might not want to jump into another chemo-like regimen.

For them, they sometimes prefer zanidatamab. AE-wise, at least in my opinion it is a little bit easier to manage. But again, different toxicities. I would leave it to the provider to make that decision along with discussion with their patient.

Dr. Mahipal: Can I just ask a follow up question, like for BTC, we have two drugs in the second-line or later setting, right? Both zanidatamab and T-DXd. But say you started zanidatamab just because patient already got chemotherapy, which is a break from chemo and just pure antibody. Once, they progress on zanidatamab, would you consider T-DXd or would you consider some other chemotherapy? I guess there is no data.  

Dr. Pant: Yes, tough question, but no data, as you said. But I would biopsy them again. If they are HER2-amplified, yes, sure I would try T-DXd because I think you could sequence them. Because I think they are different mechanism of action. Like zanidatamab binds to the outside, kind of outer domain of HER2 ECD2 and 4, whereas trastuzumab deruxtecan just have a different mechanism of action. So I would definitely give that opportunity to my patient, provided they were still HER2 amplified.

Dr. Pant: To wrap up, we have talked about the now approvals, but what about the next? What do you think about emerging HER2-directed therapy that is on the horizon for patients with gastroesophageal adenocarcinoma?

Dr. Mahipal: One of the things that we just briefly talked about is zanidatamab being studied in the first-line setting in combination with chemotherapy, with or without immunotherapy. As I mentioned before, I think we can make a really huge impact in the first-line trials, or first-line treatment for these advanced patients if you have a drug which is very, very active. Hopefully, with this combination, we hope that we can have a better response rate and better outcome for these patients and ultimately leading to better survival.

In addition, there is a lot of anti-HER2 therapies being developed for different kind of cancers, especially obviously breast cancer. We hope like some of those therapies could be applied to our cancers if they come with positive, including cellular therapies as well. We will have to see what the data shows. Again, I think, primarily based on the breast cancer data and then branch out to the these other somewhat rarer cancers.

But as we mentioned, like in gastroesophageal biliary tract cancer, the rates can be high as 20% to 30% depending on the subtype of these cancers.

Shubham, in terms of the bile duct cancer, what do you think would be the future? Would we see that something in the first-line setting or what are your thoughts?

Dr. Pant: Yes, I am really excited. Again, these drugs look very active in the second-line setting. Yes, we have two trials open actually. One is for zanidatamab. This trial is frontline treatment-naive patients. They get chemotherapy with gemcitabine-cisplatin with one of the checkpoint inhibitors, with or without zanidatamab.

The interesting thing about this trial is patients could have received up to two cycles of gemcitabine and cisplatin with the checkpoint inhibitor. As you know, cycles are given day one, day eight, 21-day cycle. There could be six weeks into treatment, you could still enroll the patients just to give flexibility in this rare patient population. So super excited about trying to get in the frontline for our patients to get more options.

We also do have trastuzumab deruxtecan with rilve, a checkpoint plus a TIGIT, bispecific, PD-1/TIGIT bispecific.

Trastuzumab deruxtecan as one of the three-arm study. Third arm is standard of care, essentially. Really excited to move these therapies in the frontline setting. The trials are ongoing. If folks have these trials open or they have some trial areas near where they are, I would highly encourage them to refer their patients there or if they have it in in-house, then I would encourage accrual on these trials because they are really important trials for the field.

So, excited about that.

Dr. Mahipal: Absolutely. What are your final thoughts, Shubham?

Dr. Pant: For BTC, I think we call it the lung cancer of GI cancers, in a way. Are we trying to call it because it is a heavyweight targeted therapies, folks could argue with colorectal cancer the same thing. But I think, for our discussion, we will call it BTC because you have all these FGFR and IDH1 and immunotherapy, and now you have HER2 agents which can be targeted.

I think the future is bright and it really shows what we can do for these rare malignancies that we should not forget these rare malignancies. There are targets. Though it might be a small number but there are patients who are being diagnosed with this. I think we should really strive to improve the outcomes for patients.;

I am super excited about the future of drug development in biliary tract cancers. Amit, what about you for gastroesophageal adenocarcinoma?

Dr. Mahipal: I would say really echo your comments. The biggest thing is we need to test, test and test. I mean, so HER2 testing just kind of wrapping up, is IHC. It is very easy. Almost every single lab pathology, wherever there is a cancer center can do it. They have been doing it for breast cancer. Again, the criteria is a little bit different. They can easily apply to this gastroesophageal and BTC cancer.

I think the biggest step I think I would suggest is to do testing. It will be better if you can do a reflex testing, because I think when a patient comes to an oncologist, they have already been diagnosed for a couple of months before they actually get diagnosed with that particular cancer, and then they want to start treatment next day, while we are awaiting for these biomarker testing.

It would be great to have a system where we can do reflex testing, including HER2 and NGS testing, so that when the patient comes in, we have all the biomarker data and we are discussing with the patient what the next step would be.

Dr. Pant: Yes, thank you