Overview of BTC and Key Diagnostics

We'll go over an overview of biliary tract cancers and some key diagnostics.

            Poll 3

So in your current practice, how often do you request or verify testing for actionable biomarkers to guide treatment decisions for patients with advanced cholangiocarcinoma? So you have a patient with cholangiocarcinoma in your office, how often are you getting biomarker testing?

1. I don't do this ever;
2. I do this for select patients; or
3. I do this whenever possible.

So it seems like majority of people do this whenever possible. And some people are selective, perhaps in patients who they feel will be able to go on to targeted therapy.

Biliary Tract Cancers

Okay, so let's talk about biliary tract cancers overall. So there's some good news and some bad news. So back in 2009, gemcitabine and cisplatin showed an overall survival benefit against gemcitabine alone. And the median survival with gemcitabine and cisplatin was around 11 to 12 months.

That was 15 years ago. In the last two or three years, there have been two other positive front-line studies, and Dr. Borad is going to talk about these. And it was a combination of gemcitabine and cisplatin, which was the backbone, plus a PD-1 inhibitor, either durvalumab or pembrolizumab. And the median survival with this was around 12 to 13 months in both trials.

So overall, over 15 years, we've gotten one month of increase in median overall survival, but the good news is that we're getting better on the tail. So there are more people that are alive at two years because of the benefits of immunotherapy. That's one piece of good news.

The other piece of good news is with next generation sequencing, we've been able to identify a lot of targets. And so now in the second-line, we actually have multiple different targeted therapies that are available to give patients. So while overall it might feel like we haven't made a big stride in terms of the one month difference in median overall survival on the front line, we have many options for people in the second line, and we're getting better on the tail.

Between these three different types of biliary tract cancers, we used to think of biliary tract cancer as one big homogenous group of cancers, and if anything we thought about it anatomically, bucketed patients into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. But now, as we've gotten smarter with next generation sequencing, we recognize that these are molecularly heterogeneous subsets.

There are a couple of unique things also about these different diseases. Intrahepatic cholangiocarcinoma, as you know, involves the secondary biliary radicals and beyond. So it's tumors that are inside the liver. So diseases that affect the liver, such as hepatitis B, hepatitis C, metabolic syndrome, that cause inflammation and scarring of the liver, those increase the risk of intrahepatic cholangiocarcinoma. And then there are certain diseases that increase the risk of any of the biliary tract cancers, such as primary sclerosing cholangitis, inflammation of the bile ducts, and certain types of liver flukes.

And overall obesity and metabolic syndrome have been increasingly causing both cholangiocarcinoma and other types of liver cancer such as hepatocellular carcinoma.

Intrahepatic cholangiocarcinoma often incidentally found. Someone has a pneumonia, they get a chest CT and then the top of the liver is caught. For gallbladder cancer, a couple of things to know is it's more common in females than in males. It's also incidentally often found when people get a cholecystectomy.

Extrahepatic cholangiocarcinoma, real estate is the most important thing because these tumors tend to block the bile ducts. These patients tend to present with painless jaundice and we often can detect extrahepatic cholangiocarcinoma at a time where you can do surgery. You often detect these early.

            Biliary Tract Cancers

Biliary tract cancers are small, but mighty – are infrequent, but mighty tumors in that they're less than 1% of cases of cancer globally. But as we talked about, they're aggressive malignancies and they don't have a great prognosis. But 40% to 50% of intrahepatic cholangiocarcinomas have some sort of actionable alteration. About 10% to 30% of extrahepatic cholangiocarcinomas have an actionable alteration. And about 20% to 30% plus of gallbladder cancers. And these numbers are increasing over time.

            Targets in Biliary Tract Cancer

And as you can see, these are the different types of alterations that we see. So what are the two that I want to highlight? I want to highlight FGFR2 fusions and IDH1 mutations. These are the two that at least in intrahepatic cholangiocarcinoma you see in more than 10% of patients. And so these are two that we look for a lot. That's why they have the biggest circles.

And then there are other alterations like NTRC fusions, which certainly have good drugs for them, but they're very infrequent. NTRC fusions are seen in less than 1% of biliary tract cancer. I've been taking care of biliary tract cancer for over 10 years. I've actually never seen an NTRC fusion positive biliary tract cancer, but they certainly exist in the trials.

And then as you can see on the left, we have what it looked like in 2020. These were the targets that we had available with drugs. And on the right, it's from 2023, we're overall being able to identify more targets. So I'm going to talk a little bit about a case with FGFR2 fusions. Dr. Borad is going to talk about a case of a patient who had an IDH1 mutant tumor and another one that had a BRAF V600E mutant tumor.

And Dr. Harding is going to talk about a patient with HER2 amplification. So we'll talk about the different drugs that are FDA approved and available for these different patients.

            Guideline Recommendations for Molecular Testing in Advanced Biliary Tract Cancer

And the question is, what tests should you choose? There's so many different tests out there to identify different alterations. What I would say in cholangio is oftentimes you get a scan sample. I don't know if people have had the experience where you do a biopsy, but then in the end the tumor is too necrotic. And when you try to send for molecular sequencing, it comes back as quantity insufficient.

And so it's because it's necrotic that you don't have enough DNA to be able to do the sequencing. So whenever I do sequencing, I try to do it on a panel that tests for all the major alterations that have targeted therapies against them.

So as you can see on the left, a variety of different alterations. The next column, you can see the incidence of all of these. And the bottom three, FGFR2 fusions, IDH1 mutations, and HER2 amplification overexpression are the three most common.

On the right, overall, next generation sequencing panels are generally the way to go for cholangiocarcinoma, and there's some that you can track with FISH or IHC.

            Role of Liquid Biopsy for Detection of FGFR2 Fusions and IDH1 Mutations in BTC?

And then, as we talked about, sometimes you do a biopsy, but you still can't get enough DNA in order to be able to do the sequencing. And somewhere between 15% and 25% of samples in intrahepatic cholangiocarcinoma, we fail to be able to identify the genomic profile based on tissue testing.

And one thing I always ask our interventional radiologist is can you please do a core biopsy instead of doing an FNA? Because FNA often does not give us enough tissue. But in any case, even when you do a core biopsy, sometimes because it's necrotic, you don't have enough, so we can do liquid biopsy. And so Dr. Borad and Dr. Harding have both done a lot of work in this area around liquid biopsy for cholangiocarcinoma.

And this was a study that was a collaborative study across more than 10 institutions with Guardant360, it’s a company that does liquid biopsy, as many of you know. And we looked at about 1,700 patients that had biliary tract cancer. And we found that 44% of those patients had some sort of actionable alteration caught on liquid biopsy. But a key thing to know about liquid biopsies is they're good at picking up some alterations, not great at picking up other alterations.

So in this study, Guardant360 was very good at picking up IDH1 mutations, but it wasn't as good at picking up FGFR2 fusions. Over time, the liquid biopsy companies are getting better at picking up fusions, but in general, if you have a patient do a liquid biopsy, you don't see a fusion, recognize that it can still be present, but just did not get picked up on the biopsy itself.

            Assessment 1

Okay, so now going back to the first question we ask. Which of the following actionable alterations meet two criteria? One, they're seen in more than 10% of patients, and two, they influence targeted therapy decisions.

            Assessment 1: Rationale

Okay, overall, people – some people said FGFR2 fusions only. Some people said IDH1 mutations only. Actually, the gray is the post. I got you. Okay, so 75% of people said the correct answer, which is FGFR2 fusions and IDH1 mutations. So that's right. For anyone that said NTRC fusions, those are seen in less than 1% of patients, but the FGFR2 fusions and IDH1 mutations, those are the ones in intrahepatic cholangiocarcinoma that you see in more than 10%.

I'm going to throw a question real quick to Dr. Borad and Dr. Harding. How often when you do a biopsy with patients with intra – with patients with intrahepatic cholangiocarcinoma.  One, are you seeing people getting FNAs instead of core biopsies? And two, when people get core biopsies, how often are you seeing that you're not able to use tissue-based genomic profiling and then you move to liquid-based?

Dr. Mitesh Borad: Yeah. So clearly, core biopsy will be referred, reduce the chance of not getting sufficient material. And when you get the biopsy, you can have an impact. If it's after initial therapy, it may have a higher chance of having necrotic lesions and having a lower chance of yielding on ultimate results. So if it's upfront with core biopsies, probably 5% failure and be a bit higher if you do it later.

Dr. James Harding: Yeah. I agree with that, generally correct. We tried to do core biopsies on these patients to have sufficient tissue for all of these necessary molecular studies.

Dr. Goyal: Sounds great. Okay, now moving on to some case discussions.

            Systemic Therapy for Unresectable and Metastatic Biliary Tract Cancer

So overall, when I have a new patient with biliary tract cancer that comes into my office, I will often draw a picture of these three buckets, and I will say when we treat advanced cancer, overall we have three different options: chemotherapy, targeted therapy, and immunotherapy, as we all know as medical oncologists and APPs in the room.

And overall, I just go over sort of how these different drugs work and how cytotoxic chemotherapy and targeted therapy attack the cancer itself and how immunotherapy overall boosts the immune system against the cancer. So they work in different ways and therefore have different side effect profiles.

And the good news is in biliary tract cancer, for a long time, as I mentioned, we just had chemotherapy, but now we have options from all three of these buckets. And the five cases that we're going to highlight are going to talk about how we're going to dip into all of these buckets.

Case Presentations in Advanced BTC            

So for the first case, I'm going to turn it over to Dr. Borad.

Dr. Borad: All right. So again, good evening to everyone. Thanks for coming. And appreciate CCO organizing this event and our sponsors for their support of the activity. So we'll start with cases as Dr. Goyal highlighted.

So the first case will be in patients who have not yet received systemic therapy and these are patients who have locally advanced or metastatic disease.

            Case 1: Treatment-Naïve Extrahepatic Cholangiocarcinoma

Okay, so this case we have a 34-year-old male originally from Thailand, who presents with painless jaundice, one of the ways as Dr. Goyal described that you can have disease presentation. There's also some mild right upper quadrant tenderness to palpation. Labs as you can see with chemistries, liver tests, you can see the bilirubins somewhat elevated there.

On imaging there's some biliary dilatation in the region of the head of the pancreas with multiple lung nodules that are approximating a centimeter. There's a stricture in the distal common bile duct. You can see the immunohistochemistry profile consistent with epithelial tumors. And you can see some markers that are negative for what you would expect if it's colorectal cancer or lung cancer or thyroid cancers.

And based on this, the diagnosis was ascribed to be metastatic extrahepatic cholangiocarcinoma. So of course, the elements that go into the diagnosis are a constellation of clinical findings, tests, and histology.

            Poll 4

So in your current practice, which of the following treatments would you recommend for this patient? And you can see the options are:

1. Gemcitabine + Cisplatin, what we would refer to as gem-cis;
2. Gem-cis with durvalumab;
3. Gem-cis with pembrolizumab;
4. Nivolumab and Ipilimumab; or
5. Pembrolizumab.

Okay, so a lot of gem-cis-durva favor – favoring here, and then some with gem-cis-pembro, and a few people with gem-cis, and single agent or doublet immunotherapies not chosen at all.

            Systemic Therapy for Unresectable and Metastatic Biliary Tract Cancer

Okay, so let's see what the data would tell us to do. Of course, this draws from two buckets, the cytotoxic bucket using gemcitabinin and Cisplatin, and the immunotherapy bucket, which would be the checkpoint inhibitors, either duvalumab or pembrolizumab in this case.

And of course, given different scenarios, you may modify this in certain situations and use other platinum agents, although that would be extrapolation.

            Historical Data for Frontline Treatment of Advanced BTC ABC-02: Gemcitabine + Cisplatin vs Gemcitabine  

Okay, so historical data is derived from the ABC-02 study that was conducted in the UK. And this set, the standard of care at the time, as was alluded to by Dr. Goyal. So gemcitabine and cisplatin versus gemcitabine. You can see that it's almost a one-year median survival compared to eight months. And it also won on progression-free survival and overall response rate. The separation of the curves early and it persists. But there's really no long-term survivors typically, so there's not really a tail with this kind of regimen, which is what we'll talk about it with the immunotherapy studies.

            TOPAZ-1: Durvalumab and Gemcitabine + Cisplatin in Patients With Advanced BTC

Okay, so the first study is TOPAZ-1, which used durvalumab in combination with the cytotoxic doublet. So this was a phase III study conducted in a global fashion. And gemcitabine and cisplatin was the standard dosing that's used, the 1,000 and 25 milligram per square meter respectively, days one and eight.

Durvalumab was flat dosing versus placebo. And after six months, there was the provision to use maintenance durvalumab, or here obviously as maintenance placebo. Primary endpoint was overall survival. Secondary endpoints were other efficacy and safety endpoints. And there was some assessment to look at PD-L1 status and other factors which could potentially be biomarkers.

            TOPAZ-1: Efficacy

So you can see that the separation of the curves really didn't happen till about six months in this study. And the median overall survival difference is only a little over a month, but that's not where the story is with immunotherapies. While this was statistically significant, the landmark events are more meaningful. So at one year, 18 months, and 24 months, you can see that the separation increases progressively, and you have this tail that's about 10% to 12% to 15%.

So in immunotherapy studies, really the metrics should be these landmark events and not so much the median survival.

            TOPAZ-1: OS Subgroup Analysis, Anatomical Subsite

In terms of subgroup analyses, the vast majority of the subgroups had benefit other than a few geographic subgroups shown here, and they didn't really have a large number of patients. It may have been difficult to see things from that perspective. So, again, immunotherapy, you would expect that it would have broad applicability.

            TOPAZ-1: OS Subgroup Analysis, Mutation Status

If you look at the genomic alterations, which is a legitimate question, I was actually surprised that it did not matter which genomic alterations you're talking about. For the most part, you had benefit across the board, even in those subgroups that have, you know, what are clearly driver events and strong ones, such as FGFR2 fusions or rearrangements.

            KEYNOTE-966: Pembrolizumab and Gemcitabine + Cisplatin in Patients With Advanced BTC

And then the second study would be, if you're a pembrolizumab user and you use it a lot in your own practice for other cancers, it may make sense to draw from here. So this was gemcitabine-cisplatin with pembrolizumab versus placebo. One of the big differences here was that instead of having this maintenance phase, you could continue all three drugs in the experimental arm and likewise in the control arm.

Well, primary endpoint was overall safety, same kind of efficacy, endpoints as secondary. Endpoints and safety as well.

            KEYNOTE-966: Efficacy

So here you can see some early separation of the curves, interestingly, not dramatic, but definitely some early separation. About the same amount of median survival benefit, not dramatic, less than two months. But the landmark events are where you start seeing differences and these become bigger as you go to 12 months, 18 months and 24 months. And you end up with the same kind of numbers, 10%, 12%, 15% or so at the end of the day.

            Case 1 Revisited: Treatment-Naïve Extrahepatic Cholangiocarcinoma 

So we'll revisit this case. So young man with a newly diagnosed extrahepatic metastatic cholangiocarcinoma with the laboratory parameters shown. Optimal treatment in this case, these are the three things that you could consider.

            Case Presentations in Advanced BTC

Okay, so with that I'll turn it over to Dr. Goyal and just to add to that case that I just showed, gemcitabine-cisplatin may have been a consideration for some of you because of the elevated bilirubin and that's understandable, but I think you can give all of these agents even if you have some modestly elevated bilirubin structure.

Dr. Goyal: Thank you, Mitesh. Okay, for case two, we'll talk about a patient that I took care of several years ago with an FGFR2 fusion positive cancer.

            Case 2: FGFR2 Fusion + Intrahepatic Cholangiocarcinoma

So she was a 37-year-old woman who presented with abdominal pain and was found to have a 6.1 centimeter liver mass. Her biopsy showed intrahepatic cholangiocarcinoma. A question for Dr. Borad and Dr. Harding. How often is it difficult to figure out that someone has intrahepatic cholangiocarcinoma? It's a diagnosis of exclusion, pathology doesn't have one particular IHC marker. How do you figure out someone has a primary liver adenocarcinoma compared to a metastatic adenocarcinoma in the liver?

Dr. Harding: Well, you know, I think that as you kind of stated, carcinoma of unknown primary was, I think, often a kind of a bucket that these tumors would fall into. I think there are some key characteristics though for intrahepatic cholangiocarcinoma. There are certain imaging parameters that appear classic for it.

You know, you on biopsy will often have, you know, an adenocarcinoma that has set IHC parameters. You can, if you need to, do upper and lower endoscopy. But I personally have found that, you know, really there are kind of classic findings to the disease, which often, you know, are pretty evident when you see it.

It's not like cannibal metastasis throughout the liver. So you send for all hypo attenuating peripheral enhancement, capsular retraction. And it really I think has a very classic appearance radiographically.

Dr. Borad: Yeah. As you alluded to, diagnosis of exclusion or diagnosis after sufficient workup would be the way to look at it. And as these molecular tests get more sophisticated and the reporting becomes more comprehensive, perhaps the mRNA profiles and micro-RNA profiles will already give you the diagnosis and you won't have to do as much a workup as you did in the past.

Dr. Goyal: Yeah, absolutely. I think it would be great if we can get the genomic profiles back quicker because I often think of FGFR2 fusions and IDH1 mutations as both diagnostic and therapeutically relevant in that if I see an FGFR2 fusion, pretty much always think this is probably intrahepatic cholangio and same with IDH1.

You can sometimes see it in pancreas cancer. You can sometimes see it in colon cancer, but not very commonly. So if I see a dominant liver mass, then I will often think it's intrahepatic cholangio. I do sometimes get a PET scan if I just want to make sure there's no primary elsewhere.

So she underwent resection, and then she had six months of adjuvant therapy. She unfortunately had a recurrence 18 months later. She then went on to gemcitabine and cisplatin. This was before the era of durvalumab and pembrolizumab. And her tumor molecular profiling showed that she had FGFR2 fusion.

So in each of these cases, we're going to ask you what would you do in this patient?

            Presurvey 3

So in your current practice, which of the following treatments would you recommend for this patient? So it seems like most people chose futibatinib or pemigatinib, and a few people chose a couple of other options, including FOLFOX, because we know there's the positive data for ABC-06. So Dr. Borad and Dr. Harding, you have a patient who has an FGFR2 fusion positive cancer, and then they have progression on first-line therapy. How do you choose between doing FOLFOX versus doing an FDA-approved FGFR inhibitor like futibatinib or pemigatinib?

Dr. Harding: I don't really think there's much of a choice. I would go with the targeted therapeutic. Often people think in terms of a randomized study showing some endpoint, like an OS benefit, that might be preferred. I think if you looked at ABC-06 carefully, you'd acknowledge it's pretty minimal to modest antitumor activity. And although both pemigatinib and futibatinib are based on, you know, single-arm phase IIs, it's a compelling response rate with really very durable disease and favorable OS.

So I would – if I knew there was a fusion, I would think of trials and/or standard of care therapy in that space with FGFR inhibition.

Dr. Borad: Yeah, I agree. I think with the known driver, the vast majority of physicians and I would say even patients would say, let's just go for the event that I have, why give me an unselected therapy? So not surprising that that's what most people chose.

Dr. Goyal: Yeah, I would agree. I find that when I give first-line therapy, about 50% of people get to plan B and then only about 25% of people get to plan C. So I try to use my best options as plan B and I always have FOLFOX in reserve if I need it or another FGFR inhibitor on a clinical trial.

            Approved FGFR Inhibitors for Advanced Cholangiocarcinoma: Key Phase II Trials   

So what are the data for the two different drugs? So again, in 2009, the data for gemcitabine-cisplatin were presented here at ASCO in a major presentation by Juan Valle. And then in 2020 was the first time there was an FDA approved drug ever in cholangiocarcinoma, and that drug was pemigatinib. And that was followed two years later in 2022 by an FDA approval of futibatinib.

These are two FGFR inhibitors that work slightly differently. Pemigatinib is a reversible FGFR inhibitor. It binds to the receptor and comes off. It binds to receptor and comes off. Futibatinib, I describe it as a pit bull to my patients. It binds to the FGFR inhibitor. It's a covalent inhibitor and it doesn't come off.

Overall, these two drugs were tested in patients with cholangiocarcinoma with FGFR2 fusion or rearrangement who had progression on at least one prior line of therapy. Pemi was in all patients with cholangio. Futi was only in intrahepatic cholangiocarcinoma, but even in the pemi study, it was mostly intrahepatic cholangio.

You can see the response rates were 36% and 42%. We cannot compare these head-to-head because they were two, as Dr. Borad – as Dr. Harding mentioned, two trials that were single agent, single arm studies, but we just have them here just so we can present all the data together.

The median duration of response on pemi was 9.1 months, 9.7 on futibatinib. You can see the progression-free survival was 6.9 and nine months, respectively, and the median OS was around 21 to 22 months in both. So overall, very comparable data. And these are two FDA approved therapies that we use today.

Dr. Borad, Dr. Harding, if you have a patient and you're looking at second line therapy, do you have a way of thinking about pemigatinib or futibatinib? Any advice for the audience members about how to choose?

Dr. Borad: From a biological perspective, futibatinib would have lower probability of developing resistance alterations for that group of patients that have polyclonal FGFR2-based resistance that emerges. But you can see from the numbers that, from a clinical, practical perspective, you wouldn't be wrong if you chose either.

Dr. Goyal: Thank you very much. Yeah, so futibatinib, there's some preclinical data showing that some of the common resistance mutations that arise as mechanisms resistant to pemigatinib, the futibatinib can overcome that. So that might belie potentially some of the numbers that we see here, but overall the numbers are pretty similar.

            Systemic Therapy for Unresectable and Metastatic Biliary Tract Cancer

So this was from the targeted therapy bucket.

            Presurvey 3

And so going back to the same patient, if you see a patient with an FGFR2 fusion positive tumor, which of the following treatments would you currently recommend?

            FGFR Inhibitors: Unique Class-Specific Adverse Events

Thank you very much for the team back – the team in the back for helping with the slides. So FGFR inhibitors, a unique class of – and there are some unique class-specific adverse events to remember. What are the safety things you have to think about?

There are two things to take away from today's presentation. One, hyperphosphatemia is something that we see commonly because you want to be inhibiting FGFR2, but these drugs inhibit FGFR1 additionally. It's an on target off tumor toxicity. And when you inhibit FGFR1, you end up holding on to phosphorous in your kidneys and in your gut. And so that leads to hyperphosphatemia and somewhere between 60% and 80% of patients get hyperphosphatemia.

Luckily, it's not a clinically significant issue for the vast majority of patients, just an abnormal lab value. But if you have high phosphorous and for example, high calcium, you could end up getting crystallization with kidney stones. You can get calciphylaxis with different kinds of deposits in your skin and your muscles. You can get deposits behind your eyes, in your heart. I've seen both calciphylaxis and kidney stones in patients, especially in people who have impaired renal function.

And the second thing to really know about is this issue of retinal detachment. So all my patients who go on FGFR inhibitors, I get a baseline ophthalmologic exam. And then if anyone complains of floaters or shiny lights, I often will send them back to ophthalmology. Luckily, they'll sometimes just see a little bit of retinal detachment or central serous retinopathy. It's often just grade 1. And if you just stop the FGFR inhibitor for a couple of days, you can often restart it, even at the same dose, and then people do fine going forward.

If the symptoms recur, I again send them back to ophthalmology and then I'll often dose reduce. Some of the other things that happen with FGFR inhibitors are, they are tyrosine kinase inhibitors, so people can get mucositis, they can get hand-foot syndrome. But they also can get some changes in their nails, some hair loss, and dry eyes and dry mouth are really common.

Anything else on adverse events for FGFR inhibitors Dr. Harding and Dr. Borad?

Dr. Borad: Some diarrhea and nail changes. A lot of these patients have their nails fall off. And if they know about it a priori, it may be easier for them to be able to accept those toxicities and go through treatments and get benefit.

Dr. Goyal: That's a great point, letting people know ahead of time what to expect can make a big difference in how they tolerate it.

            ReFocus: RLY-4008 in Patients With FGFR Inhibitor-Naïve Cholangiocarcinoma With FGFR2 Alteration   

Great. And so then we also have some new FGFR inhibitors on the horizon. So one is this FGFR2 specific drug, which it is a covalent inhibitor of FGFR2 specifically. And again, we're dealing with FGFR2 fusions. This is a drug called RLY-4008. Dr. Borad was one of the presenters of data for this molecule.

So in patients who have never had a prior FGFR inhibitor, this showed an overall response rate of 63% in the phase I study at a variety of doses. And remember, with pemigatinib and futibatinib, it was around 35% to 40%. And if you specifically looked at patients who were treated at the dose of 70 milligrams, which is the recommended phase II dose, 88% of patients had a partial response, and 82% of patients had a confirmed partial response.

So a really potent drug, which is quite exciting. So this is a drug that's currently in a phase II trial and we're awaiting the results. So potentially something to look out for as a new drug for FGFR inhibitor.

            Tinengotinib

And then what do you do after people have progression on pemigatinib or futibatinib? We are very happy to see seven to nine months of PFS, but then what do you do next? So we have FOLFOX as we discussed, but there's this new drug called tinengotinib, which is a multi-kinase inhibitor, which also hits the different FGF receptors. And this drug is a little bit unique in that, as you can see when you have a mutation that can occur in FGFR in response to pemigatinib or futibatinib, that mutation can interfere with the drug binding to the receptor because it's kind of like sticking an elbow out, these gatekeeper mutations, we've seen them in lung cancer as well, and EGFR and ALK.

It's like an elbow sticking out and the drug, as you can see – see if my mouse works. Right here, the drug cannot bind into the receptor like it would over here. With tinengotinib, it binds with a high affinity, so three hydrogen bonds out of two hydrogen bonds. It's got a small structure, and it binds out here so the gatekeeper mutation does not affect it as much. And it also binds to the active conformation.

            Tinengotinib for Advanced Cholangiocarcinoma  

So there is now some data with tinengotinib in patients with cholangiocarcinoma after they have received a prior FGFR inhibitor. And we're seeing a reasonable response rate of over 20%. And these are in patients who've had a prior FGFR inhibitor.

            FIRST-308: Tinengotinib for FGFR-Altered Cholangiocarcinoma After Prior FGFR Inhibitor  

So this has now led to a phase III study, which is the only phase III study of an FGFR inhibitor after a prior FGFR inhibitor, in patients who have a history of an FGFR2 fusion-positive cholangiocarcinoma and had at least one line of chemotherapy and exactly one FDA-approved FGFR inhibitor. So this is now open at several sites around the country. If you end up having patients that you've treated with pemi or futi and looking for more options, this is a two to two to one randomization for part A, looking at which dose. This is the FDA's new requirement around dose optimization.

So trying to figure out what's the best dose. And then once in part A, they figure out the best dose of tinengotinib, it's going to be a two to one randomization of tinengotinib versus physician's choice. And physician's choice is going to be FOLFOX or FOLFIRI.

            Case 2 Revisited: FGFR2 Fusion + Intrahepatic Cholangiocarcinoma  

And so now, coming back to the patient.

            Assessment 3

Once you've had this 37-year-old patient who has an FGFR2 fusion, what option would you recommend for this patient?

Okay, it looks like 100% of people chose futibatinib or pemigatinib. Excellent, that's the correct choice.

            Assessment 3: Rationale

I think we talked about this a lot. So some of these other drugs, Dr. Borad and Dr. Harding are going to talk about in subsequent cases.

            Case 3: IDH1 R132C-mutated disease

Okay, on to case three with Dr. Borad.

Dr. Borad: All right, that was a wonderful overview on FGFR inhibitors. And as you can see, there are many agents and many more coming. So definitely an exciting arena, even in a subset, in an uncommon disease.

Okay, so the other one that's at 10% to 15% prevalence, predominantly in intrahepatic, but can also be seen in perihilar and extrahepatic diseases is isocitrate dehydrogenase 1 mutations. And typically these are R132C mutations, but they could also be R132S or other amino acid changes.

            Case 3: IDH1-Mutant Metastatic Intrahepatic Cholangiocarcinoma  

Okay, so we have a 56-year-old female with ulcerative colitis, treated with gemcitabine and cisplatin for metastatic intrahepatic cholangiocarcinoma. She experienced disease progression in the form of peritoneal carcinomatosis.

You can see the liver enzymes shown here, as well as the chemistries. Genomic profiling was done on this patient. And this patient has a driver event in the form of IDH1 R132C mutation.

            Poll 5

So in your current practice, which of the following treatments would you recommend for this patient?

1. NALIRI, 5-FU + liposomal irinotecan;
2. FOLFOX;
3. Enasidenib;
4. Ivosidenib; or
5. Pembrolizumab.

Okay. Almost 80% of people chose ivosidenib. Enasidenib is an IDH2 inhibitor, so that wouldn't make sense here. Not much use of FOLFOX or NALIRI, and none with pembrolizumab. So, okay, let's see what changes after the presentation. I guess this should be pretty easy to convert to 100%. That's right, that's right. Although I was surprised that more people didn't pick the cytotoxics here. We'll want to hear from Dr. Harding and Goyal what their thoughts are.

            IDH1 Mutations in ICC

Okay, so mechanistically, what does this comprise? So everyone remembers the Krebs cycle, and if they don't, of course, you can just refer to the charts these days. So normally you have a conversion of isocitrate to alpha-ketoglutarate, which is accomplished by the metabolic enzyme, IDH1.

And when you have the mutations that are described, either there or in IDH2, you don't make alpha-ketoglutarate. And instead, you make a neometabolite, 2-hydroxyglutarate, which has several different functions. And these are interfering with the TET enzymes and also having impact on chromatin. And this leads to many epigenetic changes in a global fashion in the tumor. And you essentially get oncogenesis because of dysregulated epigenomic events, both at the methylation level and at the chromatin level. So it's both a metabolic and epigenomic target from that perspective.

            IDH1 Mutations Observed in ICC but Rarely in ECC

Okay. So some of the earliest studies were actually done at MGH in the cohorts profiling these tumors and they identified that it was a recurrent event. And you saw both IDH1 and 2 actually, you can see it was 3% here. But IDH1 was by far much more prevalent by a factor of 3 to 4 times, so about 15% to 20% prevalence.

And you can see these events in co-occurrence with other events such as KRAS, PIK3CA, P53, etc.

            ClarlDHy: Ivosidenib vs Placebo in Previously Treated Cholangiocarcinoma With IDH1 Mutation

Okay, so a phase II study was conducted and data from that study showed some responses, although not a very high response rate, but there were a number of patients with prolonged stable disease. So coupled together, this led to this pivotal trial termed ClarIDHy, which looked at ivosidenib versus placebo. And this is where the advocacy community paired with the investigator community, helped design the study so that it was patient friendly.

So even if it was ivosidenib versus placebo, a crossover was permitted. So all patients had the opportunity to receive ivosidenib, and there was a two to one randomization. So again, trying to stack the odds as much in favor of ultimately receiving the drug.

So dosed 500 milligrams once a day and it's continuous dosing so cycles don't really mean anything per se.

Here, primary endpoint was PFS, secondary endpoints were OS, response rate, safety, and other measures. And because there was crossover, of course, it may be difficult to ultimately see an OS difference.

            ClarlDHy: PFS

Okay, so you can see the curves separate right at that first scan, right? You get a tremendous separation, at least looking at the figures. But when you look at the numbers, they're not drastic. It's only 2.7 months for ivosidenib and 1.4 for placebo, but it's double. And you can see the hazard ratio is almost 40% reduction and p value is less than 0.0001.

You do see that there is a tail here, and we'll see that in the overall survival curve as well. It's also about 10% to 15%. So maybe there's things other than just the metabolic and epigenomic mechanisms such as immune effects that IDH may be manifesting its effect through, just like checkpoint inhibitors do.

            LY3410738 ± Gemcitabine/Cisplatin as First-Line Therapy for Advanced IDH-Mutant CCA

We also have second-generation IDH inhibitors, so LY31 – 3410738, has been studied both as a single agent and in combination with gemcitabin and cisplatin. You can see that this had an overall response rate of 46%, but this is in combination with gemcitabin and Cisplatin. PFS not reached and median follow-up here was short.

Unfortunately, this drug has been discontinued from further development because the monotherapy activity was quite similar to ivosidenib.

            Case 3 Revisited: IDH1-Mutant Metastatic Intrahepatic Cholangiocarcinoma 

Okay, so we'll revisit the case now. So 56-year-old female, already received first-line therapy, is having disease progression in the peritoneum. Laboratory profile looks pretty benign, other than a slightly elevated calcium. And on profiling, there's an IDH1 R132C mutation. So optimal treatment, ivosidenib, although I think there could be some debate about this. I would love to hear from Dr. Goyal and Dr. Harding if they would go straight to ivosidenib or would they consider the cytotoxic doublets? Go ahead.

Dr. Goyal: Yeah. So there's always this debate for second-line when people have an IDH1 mutation as to whether to do FOLFOX or an IDH1 inhibitor. Something that's really good about the IDH1 inhibitors and why it was okay to compare it, why patients did not know they were on ivosidenib versus placebo is that it's an incredibly well tolerated drug. People can have maybe some nausea or some GI upset, but that happens with cholangiocarcinoma often anyway.

And otherwise, for the most part, people do very, very well. So even if someone has an ECOG performance status of like two or maybe even three, like giving ivosidenib overall, people tolerate it really well. But it pretty much give stable disease, the response rate is about 2%. And so if someone has progressive peritoneal carcinomatosis, and let's say they're developing ascites and are symptomatic from it, and I want to try to give something that's going to maybe control the tumor a little bit better.

Now, FOLFOX is a response rate of 5%, but I sometimes find cytotoxic chemotherapy can control it better and works a little faster maybe than ivosidenib. So depending on how much peritoneal carcinomatosis there was in terms of the progression, I would think about FOLFOX sometimes for some of these patients.

As Dr. Borad showed, there was sort of a quick drop off at six weeks, so you either capture people or you don't. A couple of other quick things about this case is, this patient ulcerative colitis, and you can see the patient only got gemcitabine and cisplatin. So there's always that question about, in which patients do you give durvalumab or pembrolizumab?

Overall, I think as we've all gotten more experience as a community, even if people have ulcerative colitis, I think we still tend to try to use durvalumab and pembrolizumab and then support with anti-TNF-alpha agents. Or I look at have they had any flares in the last year and definitely talk to their gastroenterologist to see if we can get by with immunotherapy. But something to think about in these patients who sometimes have comorbid IBD.

And the other person – the other thing, this patient had a calcium of 12.8. And there's data now that people with IDH1 mutations have a higher rate of hypercalcemia. And so if you see that in a patient with cholangiocarcinoma, it’s something to note. And very often, patients with cholangiocarcinoma have a low albumin because they have poor nutrition and so you can sometimes miss hypercalcemia in patients with GI cancers who often have high albumin because your EPIC is not going to highlight it as red because your serum calcium is within the normal range. But if you do corrected calcium, they often have hypercalcemia.

So just a couple of quick little points about IDH mutant cholangio and GI cancers.

Dr. Borad: Yeah, no, great pearls there as well. So Dr. Harding, any thoughts on cytotoxics?

Dr. Harding: No, I think that generally I've moved with ivosedinib, but in select instances, I do think cytotoxics would have a role here first.

Dr. Borad: Yeah. I guess the question patients will probably ask is like, why haven't we just combined it and figured out. Can you give everything together?

Dr. Harding: Yeah, exactly.

Dr. Goyal: I've had some patients who have been on ivosidenib for a year or two years, so overall it's like really well-tolerated. When it works, it really works well for a lot of patients.

Dr. Harding: It would be nice to know who those people were, but we're not at that point yet.

Dr. Goyal: Absolutely.

Dr. Borad: Okay, so all right.

            Case 4: BRAF V600E-mutated disease

I figured all of you guys had it at 100% after we moved from removing the enasidenib, right? All right, so fourth case. Here we'll look at VRAC V600E. Of course, people are very familiar with this alteration, dealing with it in melanoma, colon cancer, lung cancer, and other illnesses.

            Case 4: BRAF V600E-Mutant Metastatic Cholangiocarcinoma  

So 68-year-old female with extrahepatic cholangiocarcinoma with liver and lung mets, had gotten gem-cis-durva, had disease progression at this time, laboratory parameters show some changes in the liver enzymes. CA19-9 is quite elevated. And here on genomic profiling, BRAF V600E has been identified as a driver event.

            Poll 6

So in your current practice, which of the following treatments would you recommend?

1. 5-FU + liposomal irinotecan;
2. FOLFOX;
3. Dabrafenib with trametinib;
4. Encorafenib and binimetinib; or
5. Vemurafenib.

Okay, so it's good to see that people are not picking chemo. I was wondering when chemo would be dead and we wouldn't have to talk about it. So this crowd is definitely thinking in that direction. Most people pick dabrafenib + trametinib, almost 80%. 14% picked encorafenib and binimetinib. And I think that's pretty reasonable, but it's more the absence of data doesn't help you support your argument with payers to proceed.

And then vemurafenib was 7%. And we don't know if single agent RAF inhibitors would give you similar response rate, but probably you would have higher toxicity, as we know from use with melanoma and other cancers, where single agents have had more toxicity than the doublets, actually.

            BRAF Pathway

Okay, so just looking at the BRAF pathway. We know you're going a little bit more downstream here, so it's the RAS, RAF, MEK, ERK pathway, but you're not going at the very top. You're going somewhere in the middle as your driver event. And then obviously if you don't block the MEK, you can get compensatory activation through CRAF. So you get less toxicity when you combine RAF and MEK inhibitors.

            Dabrafenib + Trametinib for BRAF V600E-Mutated BTC: Tumor Size Change and Response Duration

So in the context of a basket study, which looked at a lot of different tumor types with biliary tract cancers being one of the ones they looked at a little bit more rigorously. They looked at 40-odd patients and the response rate was almost 50%. You can see from the waterfall plot, almost 80% to 90% of patients had some tumor shrinkage. PFS was nine months, OS over a year, and duration was nine months.

And while there are some toxicities generally well managed, at least if not always they’re well tolerated. So the kind of findings you're used to seeing in melanoma and other cancers were also seen here. And this led to a tumor agnostic approval actually for this combination. So you can not only use it for this cancer, but any other cancers where you see this, where you may not even have data.

            Case 4 Revisited: BRAF V600E-Mutant Metastatic Cholangiocarcinoma 

So we'll revisit this case. So 68-year-old female with extrahepatic cholangiocarcinoma with reasonable labs there and has this driver alteration. So optimal treatment. I guess we were a little bit more generous to allow for the other doublet there too. But dabrafenib + trametinib would be the choice, given the substantial data at this point behind it.

So Dr. Goyal and Harding, any thoughts on if you had the two combinations that were listed, is the other one reasonable, or should we stick to the one that has the data currently?

Dr. Goyal: I agree with your point that in terms of payers, because dabrafenib + trametinib is FDA approved, just putting efficacy aside, it's much easier to get FDA approved drugs for patients. So I think that's a reasonable approach for patients.

Dr. Borad: Dr. Harding, anything people should look out in terms of toxicities and their management a priori?

Dr. Harding: Well, I mean, you know, with targeting the MAP Kinase pathway, I mean, there are kind of consistent toxicities. You can see some ocular toxicity, rash, sometimes fevers, fatigue. Generally, I find the agent has been well tolerated and, you know, it's really transformative for that subset.

Dr. Borad: And for ocular toxicity, this can be sometimes serious. So do you get baseline evaluations or is it triggered with the symptoms?

Dr. Harding: I have look at baseline for this as well as FGFR.

Dr. Borad: Something to keep in mind, you know, usually you won't run into it, but you can get that, you know, those few cases where you have severe ocular toxicity. So we don't always think about eye exams before, but something good to keep in mind.

            Case 5: HER2+ disease

Okay, so I'll turn this over now to Dr. Harding, who's done a tremendous amount of work in HER2 with a lot of the approval. So he'll take it from here.

Dr. Harding: Okay, great. Thank you so much. Thanks for the invitation and the attention and to my colleagues. I've learned a lot already tonight.

            Case 5: HER2-Amplified Metastatic GBC

So here's our case, 50-year-old woman with metastatic gallbladder cancer treated, as stated, with gemcitabine-cisplatin-durvalumab, had progression of disease to the lungs, liver. Laboratories as noted there. And then molecular profiling on NGS and ERBB2 amplification confirmed by FISH testing, and then on immunohistochemistry HER2 3+.

            Poll 7

So the question becomes, in your current practice, which of the following treatments would you recommend? Any you have – choices are here.

1. 5-FU + liposomal irinotecan;
2. FOLFOX;
3. Trastuzumab deruxtecan;
4. Trastuzumab and pertuzumab;
5. Tucatinib and trastuzumab; and
6. Zanidatamab.

And for the four, five and six, it's off-label or on a clinical trial, as noted. So go ahead.

Okay, good. So that's interesting. So the majority of people chose the ADC trastuzumab deruxtecan. And then a small proportion said pertuzumab and trastuzumab. And then a proportion said zanidatamab as well on clinical trials. So that's great. We'll come back to it as we go through these data.

            Trastuzumab Deruxtecan

So, okay, great. So, trastuzumab deruxtecan, we've heard a lot about this across solid tumors. It's an example, as we know, of an antibody-drug conjugate. Basically, the antigen-binding domains target HER2, as trastuzumab does. There's a linker, which then aligns – I'm going here, wrong way. Sorry, everyone. Can you just – there you go. Okay, sorry. Could you just reset the slide? I'm sorry, I don't know where we ended up here. Okay, great.

So it has a linker to a warhead, a chemotherapeutic warhead in this case is the topoisomerase 1 poison that's derived from exatecan.

            Trastuzumab Deruxtecan for Advanced HER2-Expressing Biliary Tract Cancers

And it has been tested now in a variety of solid tumors. There has been – there have been two studies that have looked specifically in biliary tract cancers, the HERB study, as well as DESTINY Pan-Tumor02. These studies really looked at patients with refractory – treatment refractory advanced biliary tract cancers with HER2 expression.

They had slightly different entry criteria. But what was consistently seen about in these is that there's an objective response rate in the total population of about 20% to 30%. When you select out IHC 3+, it's a higher objective response rate, up into the 50%.

They have PFS and OS as listed here. The main toxicity for trastuzumab deruxtecan, even though it's meant to be a sort of smart chemotherapy, you do still see cytotoxicity, neutropenia, cytopenias related probably to a bystander effect and a rare but serious toxicity would be lung disease, interstitial lung disease.

            Zanidatamab (ZW25): A Humanized IgG1-like Biparatopic Antibody

So another agent that we talked about which is not FDA approved, has been assessed in clinical trials is zanidatamab. This is a different type of molecule. It is a bispecific in that the antigen binding domains bind to separate sites on HER2. And this diagram isn't entirely correct. There's sort of an asymmetry in the antigen-binding arms that allow for really cross-linking of HER2 receptor at the surface, and there are multiple mechanisms of action by which this leads to cell death. And so it's an interesting molecule.

            HERIZON-BTC-01: Zanidatamab for Previously Treated HER2-Amplified Biliary Tract Cancer  

And zanidatamab has been assessed in a very large, for the – for this type of disease, open label phase IIb study in patients with HER2 amplified locally advanced or unresectable metastatic biliary tract cancers that progressed on a prior gemcitabine containing regimen. These patients were naïve to treatment with prior HER2 targeted therapy.

And what's really reported here is the waterfall plot demonstrating that the majority of patients have some degree of tumor shrinkage. The objective response rate in this study, which was centrally confirmed, and this is in the 2 and 3+ patients was 41.3%. Rapid time to response of 1.8 months and a duration of response of 12.9 months.

We presented data today actually showing that median duration of response has now increased to about 14.5 months. For me, the waterfall plot, you can see that there's anti-tumor activity in each biliary class anatomic subsite. Importantly, there is a difference based on HER2 IHC expression.

            HERIZON-BTC-302: First-Line Zanidatamab + SoC Therapy for Patients With Advanced HER2+ BTC

And based on these data, there's now been launched a pivotal confirmatory phase III study, which is essentially trying to move this agent into the first-line setting. In this case, the inclusion is not based on amplification, but really HER2 overexpression by IHC. You have to have 2 or 3+. Patients will then be randomized to receive is really the standard of care, gem-cisplatin-durvalumab versus the same with zanidantamab. There'll be a run in for safety and the primary endpoint will be PFS in the IHC 3+ to allow for the potential of crossover with other agents.

            MyPathway: Trastuzumab + Pertuzumab for HER2-Positive BTC

There are other studies that have looked at this, the MyPathway’s basket study looked at trastuzumab and pertuzumab. Sufficed to say this was, you know, allowed for local testing. A variety of patients were included but you again see objective responses about 20%.

            SGNTUC-019: Tucatinib + Trastuzumab for Previously Treated HER2+ or Mutant Advanced BTC

And then we have also data for TKI with trastuzumab on the study that looked at a small cohort of patients with HER2 overexpressing or amplified biliary tract cancer.

So I think the point of this is that there are multiple agents that have shown anti-tumor activity in this space.

            Case 5 Revisited: HER2-Amplified Metastatic GBC

The key sort of takeaway is right now in NCCN guidelines, pertuzumab and trustuzumab, and recently the agnostic approval of trustuzumab deruxtecan in the 3+ state, so we will see that being used. And then of course, we'll have zanidatamab looking to confirm its efficacy in a phase III, and those data have been already submitted to the FDA.

So the question here in revisiting the case is the optimal treatment. I guess here is HER2 targeted therapy. And probably at the current time, trastuzumab deruxtecan.

            Precision Oncology Is Key for Management of Advanced Cholangiocarcinoma  

Okay. And so at this point, I continue. There's no timer, so I don't know what I'm, you know. I'm just going to keep going here.

So in any event, I think at the end of the day when we look back at the lectures tonight, we see a long period where there's no active treatment for biliary tract cancers, not for a lack of trying. Really in 2017 we see really an opening up with agnostic approval for MSI-high with pembrolizumab and then a variety of basket studies for rare and uncommon entities. And then clearly now chemoimmunotherapy and the variety of targets that we talked about.

            Emerging Strategies in Targeted Therapy

But there are some emerging strategies that we should kind of talk about.

            Therapeutic Targets in BTC: Future Treatments

In terms of the tumor agnostic approvals, very rare. We know that there are a series of patients, very rare, that have NTRK fusions, rearrangements. There are specific inhibitors that are quite potent for this, larotrectinib and entrectinib, RET rearrangements, and there are agents available for this as well.

We already talked about mutations in BRAF. These are class I alterations where you can target with combined BRAF and MEK inhibitors. Obviously, HER2, the ADC approvals. We have the specific approvals for FGFR and IDH, but there are – the reality is when you look at the data, the majority of biliary tract cancer is still not targetable, but I think we're going to see that change over the next several years.

Certainly RAS is a key oncogene that has been classically referred to as being undruggable. However, with advances in small molecule chemistry and protein-protein interaction, you're now able to inhibit KRAS or degrade it, at least in the pre-clinical sense, and we have many trials that are looking at that.

And then we know a subset of biliary tract cancers have MDM2 amplification, which we'll discuss.

            Brigimadlin (BI 907828): MDM2-p53 Antagonist

And so to address MDM2 amplification, so as we know, TP53 is the guardian of the genome. MDM2 is an inhibitor of TP53. When you have active TP53, it's kind of telling cells to die if there are genomic abnormalities.

So if you can knock down MDM2, you might allow TP3 to work – TP53 to work, and thus you might have anti-cancer effect.

And so, Brigimadlin is an example of an MDM2 agonist. It's a small molecule. Sufficed – it's an inhibitor, but really it acts partially to degrade MDM2. We know MDM2 is amplified between 5% to 12% of biliary tract cancers. And a prior phase I study of Brigimadlin enrolled 10 patients and treated them either with – I'm sorry, 12 patients with monotherapy, seven with combination.

And what you can see is that there were clear partial responses here, and some of which were durable.

            Brightline-2: Brigimadlin for Advanced TP53-WT, MDM2-Amplified BTC and Other Solid Tumors

And this has prompted the Brightline-2 study, which essentially looks at unresectable and locally advanced metastatic TP53 wild-type. It must be wild-type, and you'll have MDM2 amplified tumors with – the cutoff is an eight-fold amplification, and they have set to receive prior therapies. And then they will go on to receive brigimadlin, which is an oral drug dosed once every three weeks.

And the primary endpoint of the study is objective response. There are also cohorts for pancreatic cancer because we see MDM2 amplification in the subset as well, lung and bladder. But there are other tumors such as neuroendocrine that express this.

Other endpoints for this study are as listed here. This study is currently enrolling. And it will certainly be, I think, very interesting to see the ultimate outcomes there. Main toxicities of MDM2 inhibition are well established in at least the phase I settings.

Cytopenias, nausea, vomiting, those are the key elements but in general has been safe and tolerable. So we're excited to see those data.

            Adagrasib: KRAS G12C Inhibitor

I think we only have a few slides on the very, very large topic of targeting RAS. I think really the breakthrough was, you know, the observation that you can inhibit specific KRAS G12C with small molecule by, you know, basically bridging that sulfur bond and locking a RAS in sort of its inactive form. And we see that KRAS G12C is not common in biliary tract cancers, but when you isolate those patients as seen in the KRYSTAL-1 study, which looked at adagrasib in a variety of solid tumors harboring KRAS G12C, you could see that the majority of patients have tumor shrinkage. The objective response rate in this cut was 41.7%.

And you can see a very favorable median PFS, although acknowledging small numbers. Some of these data were updated today and are now in NCCN guidelines to help for this subset.

            Assessment 2

I will – actually, before we go to the question, mention that there are a number of other molecules targeting RAS, looking at pan-RAS inhibitors, ways to degrade RAS. There are vaccine studies that are ongoing. So I do think this subset in biliary tract cancer will be served by those studies.

So our assessment is, which of the following agents is an MDM2 inhibitor with an ongoing phase II study? And I think you're supposed to answer now? Yeah? Go ahead. Do you guys know?

Okay, so everyone got it. And we have already talked about the other potential choices.

            Assessment 2: Rationale

Okay, thank you. All right. And so we've talked about this. This is the MDM2 inhibitor ongoing clinical trials. We've talked about ivosidenib as our selective IDH1 inhibitor. We talked about the unique mechanism of action of tinengotinib in FGFR2 altered tumors and zanidatamab as a bi-specific that has activity in HER2 positive biliary tract cancers.

            Poll 8

Okay, so I think we're wrapping up the sessions now. So the polling questions are, do you plan to make any changes to your clinical practice based on what you learned today in today's program?

1. Yes;
2. No; or
3. Uncertain.

So I guess not. I don't know. There’s – it's not coming up, but I assume that you will. Okay. So – sorry about this.

            Poll 9

So then where last question if you go back is, enter one key change that you plan to make in your clinical practice based on this educational format today. Thank you.

All right, I think it's your turn.

Q&A

Dr. Goyal: Thank you Dr. Harding and Dr. Borad. Those are excellent presentations. So overall in the last seven minutes we'll go over some of your questions. So there are a couple of questions about first-line therapy, and I'll bucket them together. So one is, do you generally consider – I mean continue, gemcitabine and immune checkpoint inhibitor after eight cycles of the triple therapy? When do you stop? How do you make that decision? That's one question.

And the second question around that is with first-line chemotherapy plus immunotherapy, can either treatment be paused in a patient who's having an ongoing response. So overall, how do you make decisions around first-line therapy when you have starting with the triplet?

Dr. Borad: Yeah, this comes up a lot, right? And the TOPAZ-1 has one study had the maintenance approach and the KEYNOTE-966 allowed for continuation. So I always generally tell people follow guidelines, but don't be too robotic. Make decisions that are rational and make sense for your individual patients. If they're having nephropathy, of course, you can continue – discontinue the cisplatin. If they're tolerating things well, you can discontinue gemcitabine and checkpoint inhibitor.

You're not tolerating chemo well at all, you can just go to the immunotherapy. You don't need to start dialing down at six months because often what happens is patients start progressing again and you don't know why they were benefiting in the first place. So it's not uncommon that we tell patients to go back on the chemotherapy.

Dr. Goyal: So overall, what I'm hearing you saying is the guidelines are when you're doing durvalumab, you do gemcitabine-cisplatin-durvalumab for six months and then durvalumab alone every four weeks. And when you're doing gemcitabine-cisplatin-pembrolizumab, you do six months of the triplet therapy and then you do pembrolizumab and gemcitabine together as your maintenance. That's the guidelines.

But depending on the patient's situation, you might continue chemotherapy longer or stop chemotherapy sooner.

Dr. Borad: Precisely.

Dr. Goyal: Yeah, it sounds great.

Dr. Harding: I agree with that. I mean, I think the totality of the data would suggest that you have the flexibility within the guidelines that are presented.

Dr. Goyal: Another question that comes up often for our patients is, Dr. Borad, you presented a patient first who had a high bili. And so the question is, in this patient, do you place a stent? And then what do you biopsy in a patient with extrahepatic cholangio? And how do you do that biopsy? Do you tend to biopsy the primary in the biliary tree, or do you tend to biopsy a suspected met, like that patient in peritoneal carcinomatosis? And if you have someone who just has extra-hepatic cholangio, what's the best way of biopsy-ing that tumor without – if they don't have any mets?

Dr. Borad: Yeah, that can be difficult, right? So extrahepatics and perihilars, it may be difficult to get core biopsies. Unlikely, you'll get them through percutaneous approaches, you'll likely have to do endoscopic approaches, in which case core biopsies will likely be out of the question. So you may have to go to some of the other ones, but that patient I think had only mets that were about a centimeter, so they – even those might not be enough. So that's where the role of liquid biopsy and these other measures is very critical. So always think about getting both if you can, not just one.

Dr. Goyal: And how about stents? Stents come up a lot for our patients.

Dr. Borad: Yeah. I mean, this is definitely a multidisciplinary disease and getting them to see your gastroenterology colleagues early on is very critical. Knowing that they have stents in place and need to be exchanged is critical. And often if you're going to put stents in and they have metastatic disease, the de facto is to go with metal stents to begin with instead of putting plastic.

Dr. Goyal: Great. A question about toxicity. With the FGFR inhibitors, we talked about hyperphosphatemia not being clinically significant in most patients. Do you really need to check it? How often do you check it? And then also someone said, we have limited experience, but few patients experience bone pain and nail toxicity just within two weeks of FGFR inhibitor treatment. Is this type of really early type of toxicity reported and why do you get that?

Dr. Harding: Yeah, I mean, I think the nail bit toxicity, frankly, is challenging to manage. And we tried to really align the patients with our dermatology colleagues to see if that will help, but I find it hard to manage that and over time it will improve and stabilize. It almost dries out, if you will.

In terms of the hyperphosphatemia, I do monitor it with every cycle and sometimes even more frequently when I start. I don't find like the slight elevation of five to seven overly worrisome, but as it goes higher than seven, I'm likely apt to start a phosphate binder and to monitor it more closely.

I think the initial experience on the studies was that we've been very aggressive at trying to lower the phosphorus, and that caused an opposite problem that was also challenging to manage. I don't know what you do?

Dr. Borad: Yeah, and I think you made a great point, Jim, about, again, looking at this as a multidisciplinary therapy, even though it's an oral therapy, and getting your colleagues from dermatology and ophthalmology involved from day one, and helping follow them proactively instead of going to them when you start running into trouble, and maybe even using prophylactic measures instead of trying to treat after you've seen symptoms develop.

Dr. Goyal: Yeah, we recognize cholangiocarcinoma is not that common, and then FGFR2 fusions are not that common within that, so people probably don't have tons of experience with FGFR inhibitors. There was a recent paper with futibatinib that showed the safety profile of it, and specifically went over what are short-term toxicities, like hyperphosphatemia, and then what are longer-term toxicities. And so it'll give you a sort of a flavor of what to tell patients about what to expect early and what to expect later, and it actually has very specific expert-dictated guidelines around how to manage hyperphosphatemia, nail toxicities, eye toxicities, and that was in CCR earlier this year that you can check out.

A question for Dr. Harding. If HER2 is amplified, why do you confirm it with FISH or IHC? And second, do you retest for HER2 amplification or expression at the time of progression on an HER2?

Dr. Harding: Yeah. I think that's a good question. So, you know, from the data, it seems that really it's the IHC 3+, the protein overexpression that's really critical for response. And you can see that this is what trastuzumab deruxtecan, its indication is 3+, IHC 3+.

So I do think it's important to still know IHC status. Often amplification does align with overexpression, but it's incomplete. I do rebiopsy and test HER2 again at progression. Because HER2 is very heterogeneous in its expression, and I think you may still retain it, and you see that in gastric cancer, you see that in colon cancer, and you may be able to sequence those therapies in those patients that retain HER2 overexpression.

And even from the studies with T-DXd, for example, there was about 12% to 14% that had prior HER2 targeted therapy, and they still had some responses. So it's possible that you can sequence this. And so I find that important to know that information. What are your thoughts?

Dr. Borad: Yeah, those are excellent points. I think something that might come up is if you did NGS and it was negative, should you do other tests to see if this patient is HER2? And potentially it may make sense to still do an IHC because there can be false negatives with NGS depending on the tumor cellularity.

Dr. Harding: Yeah. We reflex HER2 testing now in biliary tract cancer by ISH and IHC, and we also send for NGS.

Dr. Goyal: Yeah, one thing we did at our institution after trastuzumab deruxtecan was approved is that at least on GI cancers, we now get reflex testing the way we've done for MSI. All GI cancers get IHC for HER2 now going forward.

Okay, we have time for one last question. I'm going to combine two questions into one. So one, why do you do NGS on the primary tumor sometimes and not on the metastasis? Because won't the metastasis sometimes have different mutations in the primary?

And the second question related somewhat, I'm trying to connect two, is how difficult is it to enroll patients in trials of biliary tract cancer based on targeted alterations that you see on genome profiling? Because isn't cholangiocarcinoma a small patient population? You're talking to two of the world experts on enrolling trials on patients with biliary tract cancer, so this is perfect.

Dr. Harding: I think that for the trial question I mean I really, you know, believe that, you know, clinical trials are critical. And so I approach every patient as if we have a trial and we can do like clinical trial-based medicine. So I tell them about trials even if I don't have one.

I think that many of the patients we've seen this early onset cancers now are fit, they're able to do studies, there's a wealth of drugs. It's really, I think, getting the tissue early, establishing a diagnosis and trying to align them.

So I do think it's a rare disease, but centers of excellence have studies. There's now decentralized studies. So I think that it's really critical moving forward in that regard.

Dr. Borad: Yeah. It is uncommon disease. And once you start going into the less than 5% prevalence rate, it starts becoming extremely difficult to find these patients. And the trials can take excessively long. And all you're doing if it wasn't effective drug is delaying availability broadly to patients. So confirmatory trials that randomize and do these sorts of nutty things that the FDA makes you do seem like they need to be revisited, you know, if they're unable to enroll as we go through the first round of these.

Dr. Goyal: And primary versus metastasis genome profiling?

Dr. Borad: The primary will have obviously the founder events, which will hopefully persist in the mets, but sometimes you have to go where there's enough tissue. So I think you're looking for driver events which tend to be in either.

Dr. Harding: Yeah, we publish in, you know, our memorial data set of 25,000, you know, metastatic sites. I mean, generally the primary event is recapitulated in the metastatic site, and it's unusual that there's that degree of discordance. I think it's probably, you know – HER2 is probably one where there's more discordance. But nonetheless, I don't think there's a necessary issue with that. It's rather, you know, was there enough tissue available to do the molecular profile, and if there wasn't, I do seek a new biopsy if I can, as well as cell-free DNA. Use them in a complementary way. I think you all probably do that too.

Dr. Goyal: I'll make one last comment before we close. Thank you very much for those great answers. Ten years ago when I used to come to ASCO, I remember going around with my mentor to different meetings with companies. And we would say, please sir, you have this drug that you're using in pancreatic cancer, can we use it in cholangiocarcinoma? Or you have this drug that you're using in HCC, can we use it in cholangio? Because no one really knew about cholangio, no one was really interested in cholangio.

And I know Dr. Harding and Dr. Borad will echo this. Now there's so many companies that are emailing us saying, we want to try our drug in cholangiocarcinoma, or we have an ongoing study, we want to know if you're interested in it. And our calendars are full of meeting companies that want to do trials in cholangiocarcinoma. So there are so many trials out there. The landscape has completely changed. And a lot of these trials so far are incrementally helping us with two months, three months being better.

What we really want is to hit home runs. And so the more times we're able to put people on clinical trials, the more we're going to advance the field.