Introduction

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome again to “What I Tell My Patients.” This is part 8 of a 10-part series here at the ONS meeting. And this morning we’re going to talk about hepatobiliary cancers, a great topic with a lot happening. We have a great faculty today. As always, we have 2 nurses and 2 medical oncologists here to discuss this. We’re going to be talking about new developments, new research. We’ve got the big ASCO Meeting coming up in a few weeks, the big event of the year in oncology. We’ll talk about some of the papers that might be coming out. We will be talking about new treatments and some that are not FDA approved, so just check for prescribing information.

And for the clinicians here in the room all the slides you’ll see here tonight are on your iPad, also you can ask questions or present cases. There’s also a survey there. Same thing for the clinicians on Zoom. Hi to all of you out there. If you go in the chat room you’ll find these same functions. And if you take the 1-minute premeeting survey and also afterwards you’ll get a lot more out of the meeting, and we’ll learn a little bit about you as well.

We are recording all 10 of these programs for your colleagues who weren’t able to make it here, or are not watching on Zoom. We’re going to send you an email and let you know when these are all posted and ready to check out.

These are the meetings. We’re going to be continuing here at noon on myelofibrosis. And if you think it’s an unusual and esoteric disease this is going to be a great session today at lunch, believe me. And tonight we’ll finish out our series talking about GI cancers, gastroesophageal and colorectal cancer.

We have a different style of doing things. Not everybody likes it, but we know we like to make rounds, and we’re not into a lot of slides. We want to just really pick the brains of these investigators that we’ve brought here to Washington and really try to find out the cutting edge of what’s going on in cancer care in general and specifically this morning in hepatocellular cancer, cancer of the liver, as well as cancer in the biliary tree.

To try to enhance this year’s meeting we interviewed 8 nurses that we’ve worked with in prior ONS meetings that we couldn’t work out to bring here today, this week, and so we spent about an hour with each one of them talking about just generally taking care of patients. Similar themes that we’ve had over the years. We’ll show you a couple of — we created a bunch of mini videos, short-form videos, 60 to 90 seconds. We’ll be distributing them over the web over the next few weeks. We’re going to show a couple of these here today.

But as you can see in the bottom there we posted all 85 of the short-form videos that we produced after these discussions, so if you want to check it out just go to ResearchToPractice.com/ONS2024Clips. There’s a lot of great content there.

It seems like almost every cancer, in every one of these things we start out by saying this is a very unique scenario, and it really is. And we’re going to kind of provide a little bit of an overview of the field, and then we’ll get into HCC in the first part and biliary tract cancers, and along the way we’ll present a bunch of patients.

But I just want to start out with a little bit of an overview of hepatocellular cancer. Mark, can you just talk a little bit about how these patients present, and when you first see a patient — we’ll get to this video in a second, but when you first see a patient what are some of the things that you think about, and what’s the typical presentation?

DR YARCHOAN: Sure, yeah. Thanks for having me on. HCC, I’ll just give a little background, is actually the most rapidly rising cause of cancer death in the United States, so this is not some rare problem. I would say my typical patient is an older male, because males are more common, patient who presents often with symptoms from the cancer. So this is not a cancer that you can see because it’s in the liver. Most patients are not on regular screening because they don’t know that they have risk factors.

So I would say my typical patient comes in through the emergency room because of pain or yellowing because the liver’s not working well, bone pain if they have a metastasis. And I think part of the reason this is such a lethal cancer is that patients often present at a very advanced stage.

DR LOVE: So Stacey, can you talk a little bit more about the etiology? It’s very interesting in terms of how people get to develop hepatocellular cancer.

DR STEIN: Yeah.

DR LOVE: They may come through a viral route so to speak and others. Can you kind of talk about that?

DR STEIN: Yeah. Absolutely. So HCC is really a worldwide large cancer burden, and in the world the most common etiology is hepatitis B. But in the United States we tend to see more hepatitis C and alcohol related, but what’s really on the rise that I think we all need to be more educated about is HCC arising from metabolic syndrome, which we used to call NASH and is now called MASH. And unfortunately those patients are not being screened because no one is recognizing that they’re at risk for developing liver cancer. So patients with hepatitis B or C, or sometimes the alcohol-related patients have a hepatologist, that they’re doing routine screening, but a lot of the metabolic syndrome patients are not being recognized until the present later with cancer.

DR LOVE: So you both have referred to screening. Mark, what actually are you screening? How do you screen for HCC?

DR YARCHOAN: Yeah. So again, about 90% of HCC arises in the setting of underlying cirrhosis, and patients with cirrhosis, with known cirrhosis, should undergo a twice-yearly AFP and ultrasound of the liver. That’s what the current guidelines say.

DR LOVE: Alpha-fetoprotein.

DR YARCHOAN: Yeah. Alpha-fetoprotein.

Unfortunately, again, in order to get into screening programs you have to know that you have cirrhosis, and most patients, at least in the United States, have no idea that they even have this risk factor for HCC.

DR LOVE: Blanca, another thing that’s very different about HCC is how important interdisciplinary cooperation is. We’ve talked about that all week, but, I mean, really this is the disease where I think more than anything else where you really see some interesting interdisciplinary issues.

So Blanca, you’ve got the hepatologist who might be following them for cirrhosis and usually is going to need to follow them, you’ve got the medical oncologist, but you also have the interventional radiologist that have a variety of procedures they do directly on the liver. Kind of almost comparable, typical interdisciplinary, you have a surgeon, but with you guys there’s a lot of interventional radiology. Can you talk a little bit? I mean, I know you have conferences where you kind of get them together. What are some of the issues that come up within the team so to speak?

MS LEDEZMA: So we have the multidisciplinary team approach where we meet at the tumor boards to discuss these patients. And the problems that we can have is that perhaps the interventional radiologist will want to do what they do, which is to either do the local approaches versus sending them to us, to medical oncology, to start with systemic therapy. We only want to limit the amount of local treatment approach before we fry the liver, and then patients are not able to do the systemic treatment approach. And this is why it’s very important that we do these multidisciplinary conferences and review these patients so then everybody can weigh in, and patients can be referred to medical oncology and receive the systemic therapy before they’re not able to.

DR LOVE: And just to put this a little in historical context also, Mark, kind of reflecting back in terms of systemic treatment in patients who have metastatic disease or local disease that’s out of control. In the past we used tyrosine kinase inhibitors that focused on the VEGF axis, and then around 5 years ago — but we didn’t see really responses. That was the best we could do. And then all of a sudden immunotherapy came in, and then immunotherapy with atezolizumab, an antiangiogenic, and now we’re starting to see responses.

Stacey, maybe you can comment?

DR STEIN: Sure. Yeah. So it’s been a change. When I started out of fellowship we only had sorafenib. It was just 1 drug available. And so we did focus a lot more on additional local therapies because we didn’t have other options. And now that we have more systemic therapy options I think the transition point of when someone goes from local therapy to systemic therapy is not well defined, and I think we’re constantly trying to figure out how to do that better. And now there are studies that are looking at giving systemic therapy earlier in the process or even combining local therapy in later-stage patients. And so it’s — I would say that the most important thing I think we could do is have multidisciplinary discussions for all these patients to really get everyone’s input early for each patient.

DR LOVE: And keep in mind the kind of interdisciplinary input we’re talking about that you see in a tertiary center that has people specializing in HCC is one thing, but what you might have out there in the community may be very different in terms of their experience and their abilities.

Adjuvant Therapy for Early-Stage Hepatocellular Carcinoma (HCC)

DR LOVE: So we want to start to move now into the clinical presentation of this. And actually, Mandy, you have your patient who was a professional Santa Claus person?

MS WAGNER: Yes.

DR LOVE: So before you present the case can you just — before you get into it, can you just kind of give a brief of this man?

MS WAGNER: Sure. So he is a 70-year-old man, a retired engineer, but he also practices as a professional Santa. I mean full white beard, full big-bodied man. And he started losing weight, started having pain, lost over 100 pounds, eventually got to us when he had been diagnosed with advanced HCC with adrenal and bone metastases. By the time he came to our clinic he had lost over 100 pounds, was extremely weak. He lives in a multilevel home, and his wife had made him just move to one floor because she was worried about him falling.

DR LOVE: All right. Let’s hold it there, and then we’re going to get into more of this case as we go along, but just to paint a little bit of a picture related to the first comment. And again, these really go beyond HCC and biliary tract cancers to oncology in general. I’m just curious what your thoughts are. Ms Spickes commented a little bit about how she thinks about evaluating new patients.

MS SPICKES: Their social situation is very important. Trying to figure out what kind of family support they have, what kind of economic support they have. Do they have enough finances and people to help them get back and forth to their treatment? Do they have insurance? Do they have prescription coverage to help get their medicines? So the social environment is a big part. And I think we tend to forget that.

But we also try to find out, are you still working? Do you plan on working while you’re on treatment? And if you’re not, do you have the resources to be able to buy your food, get gas to get here, and all those things that we take for granted every day?

You kind of figure out pretty quick what their style is going to be, but I always tell them at the end of the day, it’s their decision. We’re here to help guide them, give them our knowledge, our recommendations, our thoughts. But we never force them to do anything. So if they want to do something that is not recommended, we have that discussion. Pros and cons, risks and benefits.

I will say, now, I really want you to be an advocate. Pay attention to your body. If nobody is listening to you, definitely be an advocate.

You have to kind of learn early on who is going to be a good advocate for themselves and maybe not the best advocate.

DR LOVE: So any thoughts about how this patient fits into the picture and his wife?

MS WAGNER: So, I mean, yes. They are very spiritual people, very grounded in their faith, but still want to try to do anything and everything they can. He has a good support system, which unfortunately I think in this population you might not always see because some of these patients do have a history of maybe alcohol dependence from cirrhosis and may not be as kind of reliable at coming to appointments or might not have that same social support that my patient did. So that, to her point, very big challenge. And I think as nurses and nurse practitioners what we can do is really home in, ask those questions, so that we can kind of come up together with our social worker. We have case managers to kind of help these patients with as much resources as possible while they’re undergoing treatment.

DR LOVE: In this room yesterday at this time we were talking about head and neck cancer. We had a patient who also lost a lot of weight from the disease. He was all happy about it, and the team was like no, no, no. We don’t want you to lose this weight. How did he feel about it at that point? Was he concerned?

MS WAGNER: Oh, very much so. He didn’t look like himself anymore. He, actually, the first day that I met him, handed me his card with his professional Santa picture on it, and you — he didn’t look like himself other than the white beard.

DR LOVE: Wow. Wow. Okay. So we’re going to come back to this case in terms of what happened, but we’re going to use it to kind of set up the structure how we think through therapy.

So Mark, this man is presenting with metastatic disease, which is different than obviously somebody who has localized disease or even small versus extensive localized. You can do surgery, you can do transplant on these patients, and you can use postop adjuvant therapy on these patients, Mark, which is a relatively new development. As we’ve been talking about all week, typically in oncology we study things late, and we move things early. So can you kind of track that out a little bit in terms of first of all what we know about using systemic therapy in early stage, adjuvant treatment?

DR YARCHOAN: Yeah. In almost every single cancer where we have highly effective systemic therapy we use those therapies not just to prolong life for advanced-stage disease but also hopefully to get patients to a cure. HCC I think is unique in that it’s the only major cancer type where we have had highly effective therapy, where at least as of today at the time of this conference we have no approved neoadjuvant or adjuvant therapy.

When I started treating HCC we only had 1 effective systemic therapy, and effective was a stretch. It was sorafenib. It was a quite ineffective pill. It was studied after surgery, and it did not improve outcomes after surgery.

But fast forward to 2023. We had our first positive adjuvant study, and it was atezolizumab plus bevacizumab, the IMBRAVE050 study, where patients who had surgery and then got a year of adjuvant atezo/bev had reduced recurrence as compared to patients who just got surveillance along. So it’s the first time we have anything positive to talk about, and you can see the curves here.

DR LOVE: And also, just to point out, because all week long we’ve been talking about disease-free survival curves and hazard rates. Notice here, yesterday we were talking about 0.3 with PARP for ovarian cancer, now you’re looking at 0.72. So the lower it is, the better it is. So now only 28%. At any point in time you can see the curves are not that far apart, so only 28%. And, as Mark points out, this is just in progression. Right now there’s no difference in survival. So bottom line is people are still kind of like not sure about whether to do it, Mark?

DR YARCHOAN: Yeah. I mean, I think these are very early data. What we don’t know is will this relatively modest difference in relapse-free survival translate into overall survival differences, so have we actually changed the trajectory of the disease or are we just kind of trading a benefit when the patients will inevitably relapse for a little bit early? We don’t have the answer. This is not yet FDA approved. I think it’s likely that at some point it will be. Whether this is ready to be routinely integrated into clinical practice my own feeling is not yet. The difference is pretty small between the curves and then the curves come together, which is not what you want to see for an adjuvant study. But early data. We need longer-term follow-up.

Role of Immunotherapy in Intermediate-Stage HCC

DR LOVE: So Stacey, another thing that we saw very recently, actually this year, again we talk about moving things up, and we saw — we talked about using TACE, local therapy to the liver, and now we’re talking about adding in systemic therapy along with that now instead of waiting for metastatic disease.

DR STEIN: Yeah.

DR LOVE: Again, can you kind of discuss — this is the so-called EMERALD trial that was just presented a few months ago.

DR STEIN: Yeah. So this was a big, randomized study of patients who were candidates for TACE, and the question was, was adding systemic therapy into these earlier-stage patients going to be of benefit. And so they received durvalumab with bevacizumab, and it looks like there’s a benefit. And what’s interesting about that is I think it’s — again, it’s hard to know, right, what is the timepoint of switching from local therapy to systemic. And in this case we’re bringing the systemic therapy in earlier.

The primary endpoint for the study was progression-free survival, and then they also looked at overall survival and quality of life in these patients. There were 3 arms of the study. So you can see here Arm A was the durvalumab along with TACE, then Arm B was the durvalumab with the bevacizumab and TACE, and then they received placebo with TACE.

And so it was a large study, and they included a patient group that’s similar to the ones we usually put on study, which I think this is an important point to remember; there are always patients who are doing very well. They have great liver function, good performance status, right? So it doesn’t always translate to all the people that we’re really seeing day to day in the clinic. But basically this was a positive study, and I think it really is going to make us all think very much now about where is that border, right, of when patients should be getting systemic therapy.

So you can see here the median progression-free survival almost doubled, which for a liver study this is pretty impressive. So the progression-free survival went from a little over 8 months to 15 months, and you can see there’s a real separation of the curves at that point, at 12 months and 18 months.

And so I think this just — there’s other studies still ongoing looking at Y-90 instead of TACE and other systemic therapies, and I think this is just the first study that’s going to show us that probably we need to be — that some patients are really going to be benefiting from doing more earlier.

DR LOVE: So we’re kind of beginning — we’re kind of painting the picture of where the therapies are, and then we’ll show you how it comes together.

First-Line Therapy for Advanced HCC

DR LOVE: But let’s move on to the more common situation, very common situation, of this patient who actually has metastatic disease. And Mark, of course, again, the first therapy that came out that really started to cause responses was atezo/bev, combining a checkpoint inhibitor with an antiangiogenic. And then we saw another study come out using 2 immunotherapies, durvalumab, similar to atezolizumab, but then tremelimumab, an anti —

DR YARCHOAN: CTLA4.

DR STEIN: CTLA4.

DR LOVE: I forgot what it was. Yeah. I’m running out of brain here.

Anyhow, can you talk a little bit about that strategy? We know more — anti-CTLA4 more from ipilimumab/nivolumab, which was used a lot in melanoma, now used in a lot of other situations, lung cancer. This is very similar to that, except the anti-CTLA4 is different. It’s called tremelimumab, with a different checkpoint inhibitor, durvalumab. And it looked pretty similar to what we saw with atezo/bev, I would say. I don’t know. What do you think, Mark?

DR YARCHOAN: Yeah, look. I think it’s wonderful that we even have options for patients. Again, when I started treating this cancer 5 years ago we had a single drug, sorafenib, and it prolonged life by about 2 months, and it never made people better. It just prolonged their life a little bit at a cost of a lot of toxicity. So the fact that we have now 2 front-line options for patients that actually have a real shot at shrinking their cancer and prolonging their life and making them actually feel better is really amazing. So we’ve made a lot of progress.

So again, patients who are candidates for systemic therapy, you really need a reason not to give either atezo/bev or durva/treme, so patients should really get a combination immunotherapy approach. And unfortunately, even in America, despite these drugs being out for a couple of years, a lot of patients continue to receive the old tyrosine kinase inhibitors in the front-line therapies.

DR LOVE: Really?

DR YARCHOAN: Yeah. So there’s data that more than 20% of patients are still getting —

DR LOVE: You always hear that. We were talking about CLL yesterday.

DR YARCHOAN: Yeah.

DR LOVE: Twenty-five percent of people are getting chemo, which is hard to believe. But really? People are getting TKIs still?

DR YARCHOAN: They are. And the question is where is this coming from. I don’t think it’s coming from medical oncologists.

DR LOVE: Well, that’s another issue here because a lot of these people end up starting out kind of being managed by interventional radiologists and hepatologists.

But as in all situations where checkpoint inhibitors are used, Blanca, there’s a whole bunch of autoimmune issues that come up. I’m curious whether you see anything different in patients with HCC. But what are some of the things — when you have a patient, most of these people are going to get IOs. What are some of the things you go through with them when you’re about to start at IO?

MS LEDEZMA: Well, first take a good history. What is their history? What is their underlying comorbidities? Do they have any history of any autoimmune conditions? Any colitis issues that is autoimmune? Rheumatoid arthritis? So really doing that good history-taking, because if we’re going to give them an IO, then they have a risk of having that underlying autoimmune condition exacerbated, so we don’t want to give them IO.

And then the education of how does the IO work. It’s going to stimulate their immune system. Therefore we can see these itises, I tell them from the top of your head to the bottom of your toes. And the importance of communication. Communication is key. Where are you at baseline and how do you deviate from baseline for the worse? Because the hope is that they’re going to get better and not worse, and if they’re getting worse then we need to start intervening quickly, and the importance of communication — of prompt communication and early intervention, and really stressing that.

And as Kimberly in the video noted who’s going to be a person that’s going to be a good advocate for themselves. And knowing who’s that person, who’s that patient? Who’s going to be a good advocate? And a person who’s not going to be a good advocate that we either use your nurse navigators, use your resources, to follow up on those patients, that we bring them in sooner, that we follow them, that we pull those questions out of them because they may not be forthcoming with symptoms.

DR LOVE: So Mark, of course we talk about complications from IOs, but this is a very interesting situation in terms of some of the choices here because you have atezolizumab just by itself or with bev, but only immunotherapy, but then you have also this treme — durva/treme, which is 2 immunotherapies, and then we were talking about ipi/nivo that’s been used. And I think, actually, there’s an ipi/nivo paper that’s going to be presented at the ASCO meeting. We’ll see. We don’t know what that shows, but the ASCO papers came out. It looks like there’s a paper there.

But you see different incidences of autoimmune problems with that. So ipi/nivo very high, like maybe 50% needs steroids. I think more durva/treme in the 20%, and then — maybe lower, 10%.

What kinds of things do you see? You were telling us that on the way here you were on the phone about a patient?

DR YARCHOAN: Yeah. I mean, these drugs are wonderful when they work. I mean, we actually — really, we think for the first time we’re actually curing some patients with advanced HCC because when patients respond to immunotherapy the responses are often very deep. But that comes at a risk of real toxicities. And the risk of autoimmune complications or immune-related adverse events is higher when you give 2 immunotherapies than 1, so certainly higher for durva/treme than it is for the atezo/bev regimen.

Durva/treme’s a pretty low systemic exposure to anti-CTLA4. Ipi/nivo is another regimen that may come out. We have a press release that it’s also a positive front-line HCC study so likely to become an option. That’s a much higher effective CTLA4 dose with a higher risk of complications. Whether there’s also more benefit we’ll have to see what the data shows. But I think it’s a sliding risk of toxicity.

DR LOVE: It’s interesting to see when you have 2 options. So many situations already this week when there are multiple options. That’s why patient advocacy is so important.

This is a pretty interesting difference in treatments here. And it’s interesting to see what it is that gets oncologists to change their minds about what to do.

Stacey, this is something just talking to people that was interesting. This just came out. You notice it’s a paper from just this February, more data from the same trial, the so-called HIMALAYA trial where they used this double approach of durvalumab and tremelimumab. And you can see that the curves — this is survival now, which is much more highly valued. You see a hazard rate of 0.78. So at any point in time 20% to 25% chance of being alive, which is a pretty significant benefit. Does that have any particular effect on you, Stacey?

DR STEIN: I mean, I just want to say, right, this is advanced HCC, and we have 4-year survival data, so that is amazing, right? We never had this before. So things have changed a lot over the last few years.

I had 2 patients on the Phase I atezo/bev study back in 2018 who had complete responses, went off treatment when COVID started and have not recurred.

DR LOVE: So there’s a tail on the curve.

DR STEIN: There’s a tail of the curve that’s just tremendous for some patients, and this study shows that also.

I think some of the difference in picking treatment is that atezo and bev was approved first, so people started to get more familiar with that.

DR LOVE: Right.

DR STEIN: But this is also a good regimen with a nice tail of the curve. And one thing we haven’t talked about yet, but I think does kind of separate the 2 studies, is the risk of bleeding with bevacizumab. And so we do screen all of our patients with an EGD to check for varices, and they could be treated according to their institutional standards, so that might be banding, or it might be using a beta blocker. But you do not want to put someone on bevacizumab who has a high risk of bleeding. And so in that case we would definitely think about this regimen as a great alternative. But I don’t know that there’s, other than the bleeding risk, a complete pathway to say which regimen is better for different patients.

DR LOVE: And when you’re in a situation where you have more than 1 option you can involve the patient.

Let’s get back to your patient. Did you kind of explain the options or just say hey, this is what we recommend?

MS WAGNER: I feel like, yeah. Definitely anybody that’s what we say is a bleeder, so somebody that we’re worried about with bevacizumab. I think Santa even might have even had some underlying hypertension issues which might have played into it. So discussing those options of —

DR LOVE: Do people balk at having to get EGD to rule out varices?

MS WAGNER: I don’t think they balk at it, but they, at least in our institution, sometimes they can be quite delayed. So we’re starting atezo and holding the bev until we get the EGD, which I’ve had some cases where we’ve given, like, 3 or 4 cycles before we’ve been able to add the bev.

In this patient, too, we were hoping to get a response quickly because he was fading pretty quick. He ended up admitted before we were able to start treatment, with AKI and just generalized weakness, PS of I mean close to 3. So it was kind of a now or never kind of a situation, and we ultimately ended up choosing durva/treme.

DR LOVE: What happened?

MS WAGNER: He’s had an amazing response. Amazing. Within 1 dose his AFP went from like over 400 to 30. He started gaining weight. His energy is back. He’s now allowed on any floor of his house that he wants. He’s gained 40, 50 pounds back and just has really kind of returned to his old self.

DR LOVE: Stacey, any thoughts about this case? And I’m curious, getting back to his family and his wife, kind of what the impact has been on them and what it’s been like for you to take care of him.

DR STEIN: So, I mean, it’s always rewarding to see somebody respond so well and know that we’re helping them. His wife, every time I see them, she’s always waiting for the pin to drop. Like she’s waiting for me to tell her something bad is going to happen. We’re getting ready to get another set of scans. She’s like, “Well, what do you think they’re going to show?” And I’m always trying to encourage her, “Be positive. He is doing so much better.” We hope that we are continuing to see a response, but she just — I think because she’s never seen her husband like that before and that he’s now doing better she’s just waiting for the ball to drop again.

DR LOVE: Interesting. Stacey, any comments about combining immune therapy? There’s also the so-called STRIDE approach. Can you comment on what that is?

DR STEIN: Well, so a couple things. So it’s amazing that this patient did well. We do see patients like this, which is always exciting. The AFP will start to drop, and that’s always a good indicator when they’re responding. So when we see that early, sometimes before the first scan, I always let patients know this is, right — this is very good, and this may mean that you’re responding well. So that’s always nice to see.

And also, just to mention, from the first study of atezo/bev they looked at quality of life, and patients’ quality of life on this regimen is good. They gave a much better quality-of-life report than on the sorafenib arm, so not only did it have a survival benefit, but patients really felt better on it.

Now you asked about the STRIDE regimen. So that basically is — for the HIMALAYA study they already knew that ipilimumab was often given in 4 doses with nivolumab in other diseases, and there’s a lot of toxicity with that. You mentioned up to 50% steroid use. So they designed this trial differently, that there’s only a priming dose of the tremelimumab, meaning that for the first cycle patients get both drugs, but then the subsequent cycles is just the durvalumab. And so with that you do get a lower use of steroids. It’s still 20%. And it is a high dose of tremelimumab in that single dose, and it is expensive. But that’s basically the STRIDE regimen, is this single priming dose of tremelimumab.

So I think we were able to get, in this patient population that probably wouldn’t have tolerated 4 doses of a CTLA4 antibody well, we get benefit of just a single dose with less need for steroid use. So it was a good balance I think.

DR LOVE: So Blanca, we talked before about the fact that many of these people have cirrhosis, and sometimes the cirrhosis actually is more of a problem than the cancer, and you have the hepatologist trying to manage that as well. Can you talk about how that plays out?

MS LEDEZMA: Yeah. So we’re always managing 2 diseases, the underlying liver disease and then the malignancies. So working with hepatology to help us, and we’re, as well, simultaneously managing the underlying liver disease, where these patients can have ascites, they can have the varices that come up, as well, and managing these varices. The lower extremity edema that they may experience, the albumin that drops as a result of the underlying liver disease and the complications.

Then at the same time you’re trying to then give the systemic therapy. And how good of a candidate? What’s the performance status? Can they get the systemic therapy based on their underlying cirrhosis and the underlying liver disease?

And so working together, working in conjunction, again going back to the multidisciplinary team approach to be able to evaluate these patients appropriately and work together to get them to the goal of systemic treatment.

DR LOVE: So Mark, I forgot to ask you. You were mentioning on the way here you had a patient who had pneumonitis from an IO. What happened?

DR YARCHOAN: Yeah. I mean, this is the challenge with these immune-based strategies is these immune-related adverse events. We have a patient admitted right now who got 2 doses of immunotherapy, and shortly after the second dose called our clinic complaining of some coughing and some fevers and came into the emergency room and was found to be quite hypoxic and unfortunately is now admitted to the hospital getting high doses of steroids and high-flow oxygen because of presumably pneumonitis from the checkpoint inhibitor.

DR LOVE: So Stacey, we were talking in another conference here about the question of whether or not people who get autoimmune toxicity actually do better in terms of the tumor. As kind of an example, maybe they have a more active immune system. What do we know about that, particularly in HCC?

DR STEIN: Yeah. So it seems like there is some advantage. So it’s challenging. I mean, I would say that also I’ve had patients who’ve had no serious adverse events who also have responded well, so it’s not that that’s a possibility. And sometimes patients almost worry when they don’t have side effects that maybe it’s not doing anything, and I tell them no, that’s not true. You could still have a good response with no side effects.

But we do know in general HCC is not different than in other cancers where, right? We know this from the first studies with melanoma that patients who have more adverse events tend to be more likely to have response, right, because we really activated the immune system. So there is some correlation with that.

DR LOVE: So Mark, also in the HIMALAYA study one of the arms was IO alone, and sometimes patients might not be a candidate for bevacizumab, or they may be in poor physical condition. In a second I want to hear Blanca, you actually have a patient who was on single-agent pembrolizumab. But can you talk about when you might use just an IO, Mark?

DR YARCHOAN: Well, just a broad statement first. The Phase III trials of durva/treme and atezo/bev were global trials that only enrolled patients who were very fit and had preserved liver function. And in many of these studies, the majority of patients were actually treated in Asia, where there’s the highest rate of HCC.

So the patients we see in clinic are very different than the patients that were on these trials, and I think that’s an important thing to just keep in mind. I mean, in my own practice, about half the patients I see are African American. Patients who are Black on these trials is less than 5% of the patients enrolled. So we do have this challenge of trying to apply studies to clinical practice.

I think patients who are fit should absolutely get a doublet because those are the regimens that give you the best survival. Those are the only regimens that actually beat the old standard-of-care sorafenib. I use very little single-agent immunotherapy with durvalumab, but I would say that’s something I’ll consider for patients who are very frail, where I think if they had an immune-related adverse event they probably wouldn’t be able to survive it, so the very frail patients where I just want to do something. Usually those are patients where we’re really talking about hospice even when we meet them, so these are very rare situations. I think in general patients should get a double therapy.

DR LOVE: Want to hear about a rare situation?

MS LEDEZMA: So I have this gentleman who’s 70-plus years old. He’s been on single-agent pembrolizumab for his disease, and he’s been doing fantastic. He’s sustaining his response. He’s tolerating it well. He’s maybe had minor Grade 1 rash, Grade 1 pruritus, but doing fantastic.

Most recently he had mild progression to a single solitary lesion. We treated it locally but are still continuing with his systemic therapy, and he’s doing great. His quality of life is fantastic, and he’s having a great life and doing well with single agent.

DR LOVE: Yeah. We talk about the tail on the curve. We were talking about it before. It doesn’t look that impressive, but when it’s zero and it goes to 20%, that means a lot to the individual patient. That’s really miraculous.

DR STEIN: Stacey, what about predictors? We see the different ways to develop HCC, so different: alcohol, virus, metabolic, et cetera. There have been postulations that maybe patients respond differently depending on what the etiology is.

DR STEIN: Yeah.

DR LOVE: Also, Mark was referring to African American. We know there’s a huge issue to get disparities in entry into clinical trials. There was a huge myeloma trial presented at the ASH meeting in December where they saw African American men — patients did not benefit from bone marrow transplant, and they’re kind of trying to figure out, is there — and it didn’t appear to be an access issue. Maybe a metabolic issue. Any thoughts about that, Stacey?

DR STEIN: Yeah. So, well, first, I think we all have to make sure that we’re including as many of our patients as possible in clinical trials, right? And so I think every clinical trial office at every institution is really trying to figure out how to engage in the community more, how to get a more diverse enrollment onto studies. I think that’s incredibly important. And we’re all aware of it now. I think we’re all trying to tackle it in similar and maybe slightly different ways. But I think engaging in our community and working on building an alliance with clinical trials, understanding the importance of clinical trials, and maybe a concern that there’s experimentation happening. But really trying to show that we really believe that this is potentially the best treatment for someone and that we’re trying to give people more opportunities. So that’s, I think, incredibly important.

As to the issue of etiology and response, I think we don’t really know. All of these trials have — except for the very first Phase I trials of nivolumab and pembro patients were not separated out in viral and nonviral etiology. And often for these big, global studies about half the population comes from Asia, which is then primarily hepatitis B, and then there’s a mix of other etiologies. So they never did a — these studies were never powered to really compare hepatitis B versus hepatitis C versus nonviral. There’s some hint that maybe the metabolic patients don’t have the same responses, but we don’t really know that. And the truth is there’s are the treatments that we have, so we’re still going to offer all of those patients combined immune therapy.

But I think it’s a really interesting area of research that we would all like to have more information on. But right now all of the patients are really treated the same regardless of etiology.

DR LOVE: So we’ve talked all week, and we’ve talked for years about the potential advantages to patients that participate in clinical trials. And imagine Santa Claus presenting 5 years earlier, right? Not going to be around very long with sorafenib. And here at least what’s going on right now.

One other case just to kind of, again, give you the — it was so interesting to see the different types of patients you all deal with. It’s really unique. Do you want to tell us about, I think it was your 70-year-old? Yeah, 70-year-old woman with alcoholic cirrhosis?

MS WAGNER: Yeah. So she had alcoholic cirrhosis. She had been sober for several years, following with hepatology, doing all of the surveillance, MRIs, AFP, and eventually developed HCC. She had a significant tumor thrombus making local therapies really difficult. She ended up getting radiation to the thrombus, but it was ultimately recommended that she start systemic therapy as well. We did screening EGD; no evidence of bleeding or varices. She didn’t really have any other comorbidities at the time, so she was started on atezo/bev.

Unfortunately, at the same time that she was diagnosed, or things were kind of progressing for her, her husband was diagnosed with pancreatic cancer and was being treated by one of our — one of the other colleagues in the practice. So just kind of navigating that situation for her was extremely difficult. We’re trying to help her cope with her cancer, as well as her husband.

DR LOVE: What was it like for you?

MS WAGNER: I mean, it’s always sad when you see. They have adult children, very supportive, finding out this about their mother, and then all of a sudden their dad has it too. And unfortunately for her she really never responded to the atezo/bev, and then at that point we did consider lenvatinib as second line, but her liver function was starting to decline pretty rapidly, and she didn’t tolerate it and unfortunately passed away pretty quickly.

DR LOVE: Blanca, any thoughts?

MS LEDEZMA: Yeah. It’s very tough when we see these patients with hepatocellular carcinoma, and the goal is that we want to provide them with the best treatment approach, and everyone has different types of support systems. But it is very challenging yet also rewarding that we get to be involved in their care.

Immunotherapy in the Management of Advanced Biliary Tract Cancers (BTCs)

DR LOVE: So we’re going to move on now and talk about biliary tract cancers, in the same neighborhood but a lot of differences, not to mention that these patients get chemotherapy, something we haven’t talked about yet because that’s not really much part of HCC. But Mark, with biliary tract cancers you also have the fact that they’re different locations. There’s gallbladder, intrahepatic, extrahepatic. Can you kind of paint a picture of biliary tract cancer, where it occurs and how people present?

DR YARCHOAN: Yeah. So HCC starts in hepatocytes, which are the most common cell type in the liver, and then biliary tract cancers start in the biliary epithelial cells, the cells that line the biliary tract that drain the liver. So they can be intrahepatic, those are the ones that start in the liver. They can be — gallbladder is kind of lumped in with the same tumor type or can be extrahepatic.

And the way that I kind of think about this is all of them are looped as they’re all biliary tract cancers, but the more you go down the biliary tract the more that they start to resemble pancreas cancer mutationally. And then the more you’re in the liver the more they kind of start to look like HCC. So it’s a bit of a continuum, but they’re all grouped together and treated the same, largely.

DR LOVE: And then there are people who pathologically they say is kind of like a mixture or something? What is that?

DR YARCHOAN: Yeah. So some tumors are called mixed HCC/cholangiocarcinoma. Cholangiocarcinoma’s another word for biliary tract cancer. And these are tumors that have features of HCC and features of biliary tract cancer. It’s about single-digit percentage of primary liver cancers, but it’s something that we all see in clinical practice.

DR LOVE: So Stacey, can you talk a little bit more? As I mentioned, now we’re talking about chemotherapy. So can you kind of talk about the typical presentation, what fraction of people actually are able to have curative approaches, and how you think through patients who are metastatic or incurable in terms of first-line systemic therapy?

DR STEIN: Yeah. So there’s a range of how patients may present, but often patients with biliary cancer are symptomatic, and so they may be having pain, weight loss, fatigue. Sometimes they present with obstruction, so it has a picture of kind of pancreatic cancer, and it turns out it’s in the biliary system. Sometimes it looks like they presented with acute cholecystitis, and then when their gallbladder comes out in the surgery it turns out that there was some cancer in the gallbladder, and it’s always a surprise, and then they have to go back and have a larger oncologic surgery. Sometimes it’s just more general like abdominal discomfort, where finally someone says let’s get a scan to look.

So unfortunately, as you can imagine with these presentations, we’re often not finding things very early. And when I think of some of the cases where we’ve found things very early it was almost incidental findings on someone who had a scan for some other reason, and they said oh, it looks like there’s something in the liver there. So when patients present with all of these systemic symptoms often, right, it’s too late to do a curative-intent therapy. So we do find some of those patients early, but a lot of the patients that we see are presenting more advanced.

DR LOVE: Before you get into choice of first-line therapy, just to come back to you, Blanca, in terms of some of the local issues that come up in these patients, obstruction, et cetera, and again, where interdisciplinary — what types of other disciplines get involved with these patients.

MS LEDEZMA: So with obstruction, these patients needing an MRCP, they need to get stented, they may need an external biliary drain, so we need our specialty services or interventional GI services, our interventional radiologists, to help us manage these patients. And then we need to monitor these patients closely because they may present with fevers. The stents get infected. Or their biliary external drains, they may get infected. They may be obstructed. They may not be draining. And the importance of educating our patients and following our patients closely. So these are issues that arise. And again, the importance of having that tightknit multidisciplinary team approach, having access to those specialists, and we can quickly get ahold of them, send them a message, and say we need this patient to be seen right away because either maybe perhaps they’re not febrile yet, but they’re having a rising in their LFTs, and that we know that they’re probably going to start to get infected with their stents.

DR LOVE: So Mark, we were talking about interventional procedures in the liver for HCC. Do you ever have those types of procedures done with biliary tract cancers? And how do you think through first-line therapy, which has been chemotherapy, but like a lot of other places, like lung cancer, now we’re talking chemo plus immunotherapy?

DR YARCHOAN: Yeah. I mean, I think the mainstay of treatment for unresectable biliary tract cancers is really systemic therapy. I think we use locoregional approaches in rare cases with specific goals, but it’s not really a standard approach, I would say, for these tumors.

Just very quickly, the standard of care for these tumors systemically was chemotherapy with gemcitabine plus cisplatin. That was our standard of care for a decade. But then really just in the last couple of years we’ve had now 2 Phase III studies that have added immunotherapy on top of chemotherapy, so the addition of either pembrolizumab or durvalumab on top of gemcitabine/cisplatin, and that’s really our new preferred front-line approach for patients.

DR LOVE: And by adding an IO are you seeing, again, long-term survivors yet, or do we know yet whether we’re going to see that?

DR YARCHOAN: Yeah. I mean, this is not HCC, so I would say this is a less immune responsive tumor type. The benefit of immunotherapy, candidly, is pretty small. There’s an update of the gem/cis/durvalumab data that was just presented at the cholangiocarcinoma meeting, really just 2 weeks ago, where there does appear to be continued separation of the curves over time. So there is a small group of patients with long-term survival, but it’s a much smaller group of patients than with HCC.

DR LOVE: Did you say it was a cholangiocarcinoma meeting?

DR YARCHOAN: Yeah.

DR LOVE: Wow. There’s meetings for everything.

DR YARCHOAN: I know.

DR LOVE: How many people were there?

DR YARCHOAN: Well, I didn’t go.

DR LOVE: You just heard about it.

DR YARCHOAN: I’ve gone every year, but someone had to stay back and care for the patients.

DR LOVE: All right. Well, let’s get back to — incredible. I remember the first time atezo/bev was presented it was like in the Asian ESMO meeting, and I didn’t even hear about it. And we had a meeting, and I said, well what’s the first-line therapy, and they go oh, atezo/bev. This was, like, 2 weeks later. I go, really? As soon as they saw the data they’re like we’re doing it. But it was like this weird meeting in Asia.

Anyhow, let’s talk about —

DR YARCHOAN: Too many meetings.

DR LOVE: Yeah. A lot of meetings. Well, going to meetings is different now, right? You can go on your phone.

So let’s hear about the 51-year-old man, a father of 3, Ms Ledezma.

MS LEDEZMA: Yeah. So we have this patient who’s a 51-year-old man who’s a very traditional man from — he’s a breadwinner, he’s very macho, and he likes to be very stoic, and unfortunately he has fairly newly diagnosed cholangio. And he was started on — he just had radiation, completed radiation and doing cis/gem/durva.

And so when educating this patient we were discussing the importance of communication and letting us know if he has a deviation from baseline, and he did not want that. He had no — he said, nope, I’m strong, I’m going to do this, and I don’t need to tell you this. I can take a lot. And really educating him and telling him the importance of needing to communicate to us. And it doesn’t mean he’s weak. It doesn’t mean that he’s not strong enough to communicate any potential adverse effects, but the importance that he’s going to be proactive in his care, and he’s going to take an active role in his care so that we could do prompt intervention and further evaluation if necessary.

So this is something that is going back to Kimberly in the video, who’s not going to be a good advocate. And this is a man who’s having a really tough time not being that patriarch for his family. And he wants to continue to work. He wants to continue to provide for his family. So really finding that balance with continuing his systemic treatment and continuing to work and being strong and not looking as weak, and then trying to also make sure that we’re monitoring him closely.

DR LOVE: You may have mentioned this, but what kind of work does he do and how old are his kids?

MS LEDEZMA: His kids are in, like, the late teens, and he’s in construction.

DR LOVE: In construction. And have you actually talked to any people in the family? Do they come with him?

MS LEDEZMA: His wife always comes with him. His wife is very supportive, always by his side, always — when it’s on the phone it’s both of them together. So she’s great, and she’s fantastic. But really still needing him to be the active participant and taking the lead and being proactive in his care is something that I feel like we might have a struggle. He’s had 2 cycles so far, but really needing him to — that we have to go down the list of questions and really making sure he’s answering them. And he’s the type of person that we’re going to have to pull out everything from him.

DR LOVE: We were talking yesterday. Katie Moore, who’s in Oklahoma in a very rural area, talking about patients not having access to food, electricity, et cetera. So these are always considerations.

How much of an issue are finances in his family and his ability to work right now, Blanca?

MS LEDEZMA: Oh. Right now. He’s okay right now, but he is concerned about finances, and that’s why it’s so important that he continue to provide for his family. His wife does not work, and his children obviously depend on him as well. So this is why, again, it’s so important that he continue to work and continue to provide.

In addition, he realized, on the insurance aspect. And so that’s going to be another problem, is if he loses his insurance he’s afraid that he’s going to have to go onto some other type of government assistance/insurance. He doesn’t want to have that gap. And so, again, working is so important for him for various layers, to provide for his family, to provide for his insurance needs, for his medications.

So it’s a very layered problem that it’s really hard for us to solve for him. We do try to provide him with the social support to see how we can best assist him. And then, again, now we have social workers that are there to assist him emotionally, but he’s the type of man that is resistant to it because he doesn’t want to share those feelings.

DR LOVE: So Mandy, we were talking yesterday about patients who have minor children or grandchildren. This is a theme we’ve talked about for many years. And I think somebody presented — you were mentioning he had teenaged children, that they had a 13-year-old daughter who kind of went crazy at school, and they had to kind of get social work involved. What about his kids? Do you know what they understand about what’s going on?

MS LEDEZMA: So the children, I have not seen them personally, but from what mom tells me they have somewhat of an understanding that dad’s sick, and he’s got a serious illness. But how serious do they understand his disease, that I unfortunately have not been able to grasp. But they seem like they’re still doing well. They’re still going to school. They’re trying to keep it as normal of an environment as possible for them.

DR LOVE: Any thoughts about that scenario, Mandy? It happens in all cancers, even with ones that we associate with older people, but you always do run into these circumstances. Any observations over the years in terms of the kinds of issues you see in children and what you see in children under the age of 10 compared to teenagers?

MS WAGNER: So, I mean, for any kid under 10 they’re not really going to understand that their parent has a serious illness that could eventually take their life, probably will, especially with these advanced malignancies, and how you would even approach telling a child, that seems impossible to me from personal — if it were me in those shoes.

So if we are lucky enough, and I think at my institution we are fortunate enough, we have resources to help us with these kids. We have kids’ programs that get — there are special counselors that deal with children whose parents have cancer, so trying to introduce to them early. Get psychosocial oncology involved as soon as you can. Give them all the support you possibly can in order to make an impossible situation maybe a touch better.

DR LOVE: Do you offer those services to the community?

MS WAGNER: Uh huh. Yeah.

DR LOVE: That’s great.

Biomarker Testing Recommendations and the Use of FGFR Inhibitors for Advanced Cholangiocarcinoma

DR LOVE: So let’s move on and talk about another aspect of biliary tract cancers that kind of surprised me as it started to evolve. Yesterday we spent an hour and a half talking about EGFR-mutant non-small cell lung cancer and the whole history of how targeted therapy in solid tumors evolved, which is an incredible story. We were talking about 10 different targets yesterday in lung cancer. And Mark, I sort of made the joke that cholangiocarcinoma’s the new non-small cell lung cancer because there’s a whole bunch of targetable lesions, surprising, to me, surprisingly. We’re going to talk a little bit about that in a second and also the whole idea of maintaining people on oral therapy. But can you kind of paint a little bit of a picture of how this has evolved and what we’ve basically learned?

DR YARCHOAN: Yeah. I love that analogy. I think I’m going to steal that actually at talks. But yeah, cholangiocarcinoma or biliary tract cancer is the lung cancer of the GI oncologist. About 40% of patients with intrahepatic cholangiocarcinoma, so the ones that are within the liver, have something actionable if you sequence their tumors. So 100% of patients with biliary tract cancer should undergo molecular testing, whether that means Foundation Medicine or Caris or Tempus, one of those companies, or whatever you use in house.

So we have a couple of drugs that are actually now approved for specific buckets of patients with cholangiocarcinoma who have specific driver mutations. So I think that the ones we should talk a little bit about are FGFR2 fusions or rearrangements, that’s about 15% of intrahepatic cholangiocarcinoma, IDH1, which is maybe even a little bit of a bigger group of patients with intrahepatic cholangiocarcinoma, and then occasionally you find other things that you can target, like HER2 or BRAF V600E or even other things that are a little bit rarer.

DR LOVE: Yeah. That’s what we’re going to go into in the rest of this conference. And Stacey, again here we’re talking about mutations in the tumor. So these are not germline mutations. These are only mutations in the tumor. Can you talk about the type of assays done? Basically the ones that Mark just referred to are tissue, but there’s also so-called liquid biopsies you can do on the blood. So how do you actually pick up these mutations, and what’s the difference between a somatic and germline mutation?

DR STEIN: Sure. Right. So all patients with biliary cancer have had a biopsy to make the diagnosis. Unfortunately, sometimes it’s just a brushing, and it’s barely enough cells to make the diagnosis. And sometimes there’s not enough tissue to make the diagnosis initially, right, and they have to go back, and it’s not uncommon for patients to need a second procedure to get enough tissue, and sometimes a third, which is challenging. And so when we have enough tissue, and they really only need a very small amount to send out to do this testing, we do a full genomic panel, right?

And as Mark mentioned, there’s a few companies that do this routinely. At my institution we also have an in-house panel that could be performed, but either way all these patients should be getting tumor profiling.

When we do the germline mutation testing, right, that’s genetic testing, and that’s why those patients need to be consented. We’re testing their DNA, not the tumor DNA. And that’s helpful in looking for certain mutations, including like for Lynch syndrome, which we occasionally see in these patients. All patients get MSI testing in GI cancers, and at my institution that’s just done reflexively without anyone ordering it. If there’s a GI tumor automatically they do this testing.

But then you can also have genetic testing done, and that’s done with a genetic counselor, and now they don’t even give a blood sample. Since COVID they often do these appointments by telehealth, and they send them a kit that they just have to put some saliva in, and there’s enough cells that are shed from the lining of the mouth that give enough DNA to do this kind of germline testing. So that’s done a little bit separately from us under genetics, right, but we’re ordering it and making sure these patients had it.

But what we’re really usually relying on is the genomic analysis that’s done on the tumor. Liquid biopsies are nice sometimes when there’s not enough tumor testing. You could potentially miss some things. Sometimes there’s not enough DNA, but they can give you often a lot of information just coming from some circulating DNA in the blood.

DR LOVE: So we’re going to get into the specifics of some of these, also examples of targeted therapy in general. And one of the themes this week has been the issue of adherence to particularly oral therapies and the issue of dose reduction when it needs to occur. And so before we get into the specifics I want to kind of get your take on that issue and how you, when you’re going to have a patient who’s going on targeted therapy, particularly that has side effects, how do you try to get the patient to adhere. I mean, it relates to HCC as well. Here’s Ms Glennie’s thoughts.

MS GLENNIE: My hope is that the longer the oral therapies are out and the more patients are on them that there will be a better understanding among the public, among our patient population, that just because something is an oral therapy that’s taken at home does not make it as harmless — or not that ibuprofen is harmless, but it’s something that can still have those tolerability issues but also needs to be adhered to.

And so when we’re starting somebody on a new oral therapy we will usually bring them back, depending on their diagnosis and what the therapy is, of course, usually bring them back within a week to make sure that they’re not having any acute issues with starting it. We’re lucky enough to have support from both our specialty pharmacy and we have a clinical pharmacist embedded in our heme clinic.

An extra layer of support and teaching. Naturally there are some patients who have lower health literacy and perhaps don’t have the family support that we may hope that folks would have for starting an oral therapy, so that’s also something that we take into consideration when we’re debating an oral home therapy versus a more traditional infusion.

DR LOVE: So Mandy, Mark referred to the FGFR fusions that are not uncommonly seen in this area, and we now have FGFR inhibitors as an example of an oral targeted therapy that can have complications. We’ll get into the specific kinds of complications, but just in general how do you think through assessing patient adherence? And how do you manage patients?

MS WAGNER: So, I mean, to her point, like understanding their health literacy, like do they understand that this is still cytotoxic and can have side effects, and you’re going to need to report when you’re having side effects. You’re going to need to report if you’re not taking it. So really getting that history from the patient and understanding what’s their understanding of what we’re going to do.

DR LOVE: All right. Well, let’s talk a little bit about these specific abnormalities. And Mark, why don’t we begin with the FGFR fusions? Can you explain what they are and what FGFR inhibitors are? And then we’ll get into the tolerability issues that come up. And maybe also just maybe — here’s a picture kind of — maybe you can comment on — you were talking about the different types of potential mutations that you can see. We’re not going to talk much about IDH today, although we talk about it all the time when we talk about AML for example. And incidentally, Ms Glennie was an AML nurse, FYI.

Anything else you want to say? You mentioned — we see up there in the top HER2. You have trastuzumab — or we have trastuzumab/pertuzumab. But we’re really going to talk about the antibody — anti-HER2 antibody T-DXd there. BRAF I guess can occur. And again, there’s a pan-tumor approval like we were talking about for HER2 in BRAF. NTRK, very, very rare, but also extremely treatable. But then up there in the top left we see FGFR, Mark. What’s that?

DR YARCHOAN: Yeah. So, I mean, I would just say very simply, a cancer is a cancer because it’s picked up some way to grow more than a normal cell. And what we do as oncologists is we try to figure out what are these driver oncogenes and then do we have a targeted therapy that turns them off. And I would say in the realm of cholangiocarcinoma one of the most common ones that we find is FGFR2.

FGFR2, I want to be specific, it’s FGFR2 fusions or rearrangements, so not mutations. Occasionally you find FGFR2 mutations. Those are not strong enough drivers to really be worth our time to target. But FGFR2 fusions or rearrangements.

And we now have specific FGFR inhibitors that block FGFR, including FGFR2. You can see that they’re up there on the screen, so I’m not going to read all those names. But pemigatinib is one of the main ones, and futibatinib is another one. And there are more drugs coming that may be even more potent and specific.

DR LOVE: So Stacey, there’s kind of some interesting tolerability issues that come up with these agents. Can you provide a little bit of an overview? It seems like every time we get into a new type of targeted area — we were talking ophthalmic issues yesterday. All kinds of issues come up that we never would imagine seeing. What have we seen with these agents?

DR STEIN: Yeah. So the one thing to remember that’s different about these drugs that we don’t usually treat is hyperphosphatemia. The second most common side effect on that trial was hypophosphatemia, which I think was from overtreating the hyperphosphatemia, but the real side effect from the drug class is hyperphosphatemia. And I don’t know if you’ve looked at a list of foods that you’re supposed to avoid if you’re trying to lower your phosphate, but it’s kind of almost everything. So when I looked at the list I said, “I don’t know how I would be able to follow this diet.” But fortunately we do have great nutritionists that work with our patients, and we can provide them a list to kind of help avoid those foods. And then of course we have phosphate binders for — because it’s hard to just manage it through diet.

DR LOVE: So we’ll just start with that, Blanca. Can you talk a little bit about that? We’re just going to begin with that part of it. What your experience is.

MS LEDEZMA: Yeah. So the importance of establishing where a patient’s baseline is with their labs, where is their phosphate to begin with. And then it is an oral therapy, the importance of getting them to come back to get their labs drawn. I know that we’re now all in the virtual visits, and patients don’t want to come in, and they want to do everything just locally, and it’s fine as long as you get those labs drawn. It’s important that we monitor those labs. And just to Stacey’s point, that we don’t keep them on their phosphate binders, that we take them off, and that we continue to monitor them closely. And then, again, to having the low-phosphate diet, that we monitor them closely. And that they understand this is a very common effect that we do see from these FGFR2 inhibitors, and that we monitor them, and then we see what happens, what’s the effect.

And then also there’s the other toxicities that come from it, like the nail toxicities.

DR LOVE: Yeah. Let’s get into that. But first, just to keep going on the phosphate, because again, obviously, we don’t talk about that much. Mark, do you see any clinical symptoms with either high or low phosphate? Or is it just a blood test thing?

DR YARCHOAN: Yeah. If it were just a blood test thing I don’t think we’d care about it. The problem is when you have high phosphate in the blood it binds up calcium and starts depositing in the body. And one of the places it can deposit is the skin, and it can cause just a horrific rash or even skin breakdown. It’s really just an awful thing to see. So we really do want to make sure that phosphorus stays in a safe range with these patients.

DR LOVE: I’m kind of curious, Mandy. Do you find that diet actually helps? I mean, do you really push the diet, or is it more the medication?

MS WAGNER: I find the diet stresses patients out like to no end, because these are already really sick patients that have advanced disease and have already lost a ton of weight, and they don’t know what to eat or when to eat. So we give them the information, try to tell them to do the best they can, but then really use the binders as much as possible and increase those doses as necessary.

DR LOVE: So Blanca, you mentioned nail changes. What do you see?

MS LEDEZMA: Yeah. So we see the paronychia, the lifting of the nails, or sometimes losing of the nails. And so preparing the patients for this, preparing our female patients for this, because it could be distressing for them to know that this is something that they’re going to see. And then it can be quite painful once they have it, so just keeping their nailbeds really short and soaking them with like half-strength vinegar soaks once their nails start to separate.

And then we can also see like the mucositis or stomatitis, preparing them for that, as well as communicating that this is a possible adverse effect. And if they start to have any signs or symptoms to start doing the medications, and we’ll send in like an oral dex.

And then, of course, the importance of communication so we can see them back, see is this what’s going on.

DR LOVE: Sometimes you hear stories, and you wonder like how difficult really it is to get through it. We were talking the other night about alpelisib, you may not know about that, but in breast cancer kind of a challenging drug. This sounds like kind of complicated, but bottom line is in your hands, in a place that really knows how to use the drug, what’s their quality of life? Are most of them okay or miserable?

MS LEDEZMA: Quality of life is fine. It’s well. But again, communication’s going to be important because I do have a younger patient who … who was having a hard time from a GI perspective, and having her come back so that we can see her and manage her and try to do some symptom management. We maximized that. And that didn’t work. We gave her a break, held her for a couple days, and then dose reduced. Letting them know that it’s not one-size-fits-all. There’s always the possibility to dose reduce.

She was saying, “Oh, I need to come off of this. I need to start considering another clinical trial, something else.” And it’s like, no, we don’t have to go to that extreme yet. We can dose reduce. We can just adjust it just a bit to allow you to tolerate it a bit better than you have been. And we did that, and she’s doing much better. She’s doing fantastic. The GI issues she was having, she’s done well.

DR LOVE: Interesting. So speaking of younger patients, just looking at this sentence gives me the chills, Mark: 39-year-old woman on futibatinib. What about her case?

DR YARCHOAN: Yeah. We’re seeing more and more young patients with cholangiocarcinoma. I don’t know. I mean, everyone’s nodding on the stage. I don’t know what the data is, but this is a phenotype in my clinic, and it’s usually young women with these FGFR2-driven tumors.

DR LOVE: Really?

DR YARCHOAN: The data shows that, actually.

DR LOVE: Really?

DR YARCHOAN: Yeah.

DR LOVE: Yeah. Tonight we’re going to be talking about the increasing incidence of colorectal cancer in young people, which is really major. But anyhow, what happened with this 39-year-old lady?

DR YARCHOAN: Yeah. She’s still on therapy with futibatinib. So the 2 FGFR2 inhibitors that we tend to use are pemigatinib and futibatinib. They’re a little bit different. The toxicities are a little bit different, but often overlapping.

And she does have some male pattern baldness that is very distressing. She has some hyperphosphatemia. We started her on sevelamer, which is a phosphate binder. Some fatigue, some GI symptoms. So it’s not been easy for her, but she does have a nice — an ongoing response.

DR LOVE: What’s her life situation? Does she have children?

DR YARCHOAN: She does not, actually. She has a partner, and this has been obviously very tough for both of them.

DR LOVE: So Mandy, I see you also have a 58-year-old woman who got another one of these agents, pemigatinib.

MS WAGNER: So she had pretty — she was on gem/cis/durva, had progression with extensive bone metastases requiring surgery. She had cord compression. So it took a while, plus she needed some postop radiation. It took a while for her to actually get started on second-line therapy with pemigatinib.

Overall she did pretty well. She had some issues with mucositis and diarrhea. Didn’t really have the nail changes. We really did monitor closely for the eye toxicity. I mean, she did — it was probably 2 or 3 cycles that things were kind of holding steady, but then you could definitely tell there was a clinical decline. The bone mets were progressing. She was getting weaker. She wasn’t eating. She spent a lot of time in bed. She would get confused.

So every time she’d come to clinic goals of care conversations. It’s like what are we going to do? Do we need to start considering best supportive care?

And what was interesting with her was that on the weeks that she took the pemigatinib, she felt a whole lot better despite like the cancer progressing. Her family said she was more engaged. She was up out of bed. So they pictured it more as that did improve her quality of life and wanted to continue it as long as they possibly could.

DR LOVE: What happened with the cord compression?

MS WAGNER: She ended up being admitted, had to have surgery.

DR LOVE: What kind of symptoms? What happened? Like how did it evolve? She had bone mets, known bone mets?

MS WAGNER: Yeah. It was thoracic spine. So she presented. Her one arm was completely numb.

DR LOVE: And how was she managed?

MS WAGNER: Surgically. They fixed the compression and then she had postop radiation. But I think she ended up getting like some rods and things in there too.

DR LOVE: Stacey, you don’t hear too much about cord compression. Any comments? Have you see that recently? And it’s considered one of the oncologic emergencies.

DR STEIN: Yeah. Absolutely. Fortunately we don’t see cord compression as much in GI cancers than in some other areas, and we’re often dealing more with issues of the GI lumen and the biliary tree. But certainly it’s important training for everyone that’s taking phone calls, and we certainly teach our fellows about all of these emergencies, right, the things that you really need to act on right away. And my teaching is always if you suspect it just start the treatment, start the high-dose steroids while you’re still waiting for the scan. But fortunately we don’t see it a lot, and often for patients that wind up having surgery there’s such a timeframe of being off treatment that things often continue to really decline at that point.

Potential Role of HER2-Targeted Therapy for BTCs

DR LOVE: So I want to bring up another form of targeted therapy that we refer to, and we’ve talked a lot about this this week. This is one of the big stories in oncology right now because just in the last couple weeks we had the approval of an antibody-drug conjugate to HER2, pan-tumor. Pan-tumor approval. Any solid tumor in a patient who’s run out of treatment options, which is certainly not uncommon, this antibody-drug conjugate, which seems to have activity in almost every one of these situations. And in breast cancer it not only works in HER2-positive, it works in HER2-low, which we don’t know about in the other tumors.

But all of a sudden, Mark, HER2 has come into the realm of almost everybody in oncology, particularly — mainly solid tumor oncology. Can you talk a little bit about how you experienced it?

DR YARCHOAN: Yeah. So HER2 is one of the molecular alterations that we certainly pay attention to for cholangiocarcinoma. It’s a little bit more common in extrahepatic cholangiocarcinoma and particularly gallbladder; less common in the intrahepatic patients.

I think a number of us have already been using just normal trastuzumab and pertuzumab. It’s one of the options if you look at NCCN based on single-arm data. Now we have this pan-tumor, as you mentioned, antibody-drug conjugate approval, so any tumor, any site as long as there’s HER2 positivity can get this drug. And exactly how we’re going to integrate it into cholangiocarcinoma practice, I don’t quite know, but it’s wonderful to have the option probably as a subsequent line of therapy for patients.

DR LOVE: It’s really kind of an amazing phenomenon. Again, we talked about it, and we had a program earlier this week just on ADCs where we were talking about it. But I can’t remember this ever happening in oncology, which all of a sudden you have a therapy that you have 1 group of oncologists, the breast cancer people, who have been using it for years, and they have the whole algorithm figured out how to use it. Now all of a sudden these other subspecialties, which are pretty siloed. In general a lot of people kind of mainly know their own stuff, and they’re like asking the breast cancer people like what do you do with T-DXd.

Stacey, how you’ve been thinking it through. The big issue here is not just the fact that it has efficacy and figure out how to do the HER2 testing, but not to mention there’s a potential lethal side effect, interstitial lung disease.

DR STEIN: Yeah.

DR LOVE: So this was dropped on everybody like in the last couple weeks. How have you been thinking it through?

DR STEIN: Yeah. So I will just say, there were some Grade 5 events on the studies with this drug, meaning that there were patient deaths from pneumonitis. And so I think it’s just a learning curve when we have a new drug, making sure that everyone, especially people that are taking phone calls at night, and hearing from these patients when they come in, if there’s a fellow called when someone’s in the emergency room.

It may not look like a lot. The ground glass starts, and it may look kind of mild compared to how we treat it maybe for other chemo-related pneumonitis, but we know now that it can progress quickly, and so those patients really should stay — start on steroids, hold the drug, and really treat it aggressively, because if you miss the early signs of it you might lose the window for treatment. So we have to be really thoughtful about that.

DR LOVE: So yeah. The breast cancer people, they have a — what they’re trying to do is pick up ILD before it’s symptomatic. As it comes into the other specialties their first thought is oh, we’ve got to start asking patients whether they’re short of breath or checking their O2 sats. But no, the breast cancer people, they’re doing scans, like, every 9 weeks of the lungs looking for anything, trying to pick it up when it’s asymptomatic.

So Blanca, it’s really interesting. You wake up one day and all of a sudden there’s a drug in your face that maybe you’re going to be giving to a patient, and you’re going to have to figure out what to do with it. I don’t know if you have actually used T-DXd or found anybody yet who’s HER2-positive, but how are you preparing for this?

MS LEDEZMA: So I have used it, not in this space. I’m very familiar with it. So we’re not scanning patients at a greater frequency, but just the importance of you can capture this ILD on just imaging alone in patients not be symptomatic, and what do you do with that? Do you treat patients? Do you continue treating them with their systemic therapy? Do you start treating the pneumonitis? And that’s the question that we’re at, what are we going to do with the situation? And of course we try to be as conservative as possible and start treating the pneumonitis and not treat the patient with their systemic therapy. But what’s going to happen in the community if patients aren’t symptomatic?

And then educating patients. Again, going back to where is that baseline. Where are you at baseline with how are you feeling clinically, and how are you deviating from baseline, because that’s going to help us in addition to the scans. And it really just boils down to education of the patients. I think that’s really the importance.

DR LOVE: So Mandy, I guess one of the things that is not so obvious is that — sorry — ADCs, most of the ADCs is really targeted chemotherapy, but it’s targeted. It’s a trojan horse concept, that you have a target, the target — you bind the target, but then there’s a chemo linker that brings in chemotherapy. So, actually, you can see chemo-like side effects, nausea and vomiting, even though it is an antibody-drug conjugate. What are you thinking — have you used T-DXd yet?

MS WAGNER: I have, mainly in esophageal cancer. We had a clinical trial looking at it for colorectal cancer as well. I have had patients...

DR LOVE: And tonight we’re going to be talking about it, exactly.

MS WAGNER: …with significant nausea and vomiting. Significant, to the point that we had to increase premedications, talk about — a lot of times my kind of go-to is olanzapine to use after treatment to kind of help with nausea. I see the effect on the blood counts, too, so we’ve had some treatment delays related to that. But yeah, I think the nausea risk is definitely there, pretty high.

DR LOVE: So interesting, Mark. We did a meeting at the GU conference, ASCO GU conference. We did a meeting on bladder cancer, and we actually showed video of a breast cancer investigator to the GU people talking about how they manage the acute nausea and vomiting. And so then afterwards the moderator went to one of the GU docs and said, “Well, how do you use — how do you approach this situation?” And he goes, “I’m going to do what she just said.” Because he’d never used the drug. And so a lot of — that’s what we’re hearing a lot. I’m curious, Mark, how you’re thinking through it. Have you used T-DXd?

DR YARCHOAN: I have. I’m very lucky. My clinic on the fifth floor of our Viragh Building at Hopkins we have investigators treating different tumor types who are all in the same provider area. So it’s kind of the fishbowl area. We all bounce ideas off each other.

DR LOVE: Yeah. I was showing a picture one of the Hopkins nurses sent us of the bridge collapse. I guess you can see it from Hopkins?

DR YARCHOAN: Yeah. I can see it from my office.

DR LOVE: Really?

DR YARCHOAN: Yeah.

DR LOVE: Wow. How has that affected your patients being able to get to you?

DR YARCHOAN: The traffic is bad.

DR LOVE: I bet.

DR YARCHOAN: My commute is bad.

DR LOVE: I bet.

So let’s talk about other forms of targeted therapy. And Stacey, Mark mentioned IDH. Can you talk a little bit about what IDH is? And also, are there any situations? We were talking in lung cancer yesterday where they use first-line targeted therapy.

DR STEIN: Yeah.

DR LOVE: And are there any of these where maybe you would use it before chemo?

DR STEIN: Right now the algorithm is for these patients with advanced biliary cancer that we still stick to the chemo/immunotherapy in the first line. And there might be future data where it makes sense to add in the targeted therapy with the first-line therapy, but until we have trial data showing that I think right now everyone is holding the targeted therapy for second line and beyond.

Unfortunately, we don’t have great second-line options when there’s no targeted therapy available. We’re just giving more chemotherapy with FOLFOX or Nal-IRI or FOLFIRI with very low response rates. But even with — for patients that do have a target found on testing, we’re still sticking with the cis/gem/durva or pembro in the first line.

The IDH mutations. Unfortunately, I wouldn’t say that it’s a very large survival benefit or response rate for IDH inhibitors. I think we have to keep chipping away, right? So none of these drugs are complete homeruns. I think they all add to the armamentarium of this disease, but I would say that we still have a lot of work left to do.

DR LOVE: So Mark, I don’t know. You mentioned there are other specialties there. I don’t know whether Mark Levis is nearby you, the AML person, but he’s the big IDH inhibitor in AML. And one of the things they see there is so-called differentiation syndrome. Can you explain what that is, and do you see that in these patients?

DR YARCHOAN: I’m probably the wrong person to talk about that.

DR LOVE: Okay. Stacey, take it.

DR STEIN: I would just say this as a general rule. There are sometimes amazing responses that you can see in the hematologic malignancies, and then sometimes one of our patients will come in, and the house staff team is concerned that we’re going to see such rapid responses to patients. And I always tell them to slow down. This is a GI cancer, and we’re probably not going to see anything resembling that. So I don’t know if there’s any case reports of that in biliary cancer, but I can say that I’ve never seen it, and I’ve never heard a colleague report that to me. So if it’s ever happened it’s very rare. We don’t see those kind of massive, right, responses at this level.

So when we say driver mutation, the truth is, none of these mutations ever have that kind of mass effect, right? We’re still kind of chipping away, and the response rates and the survival benefits are almost more like another line of systemic therapy. They’re not really home runs. So I’ve never seen that.

DR LOVE: So a final point, Mark. We talked about pan-tumor approvals, and another one is for BRAF. So if you have a — and this is a great opportunity to help your patients. Check their chart. When you see a patient with a solid tumor who’s running out of options, check their chart and see if they have a HER2 assay, see if they have a BRAF assay. Mark, what do we know about BRAF therapy in biliary tract cancer?

DR YARCHOAN: Yeah. I mean, these drugs were really initially studied for melanoma, where BRAF V600E is the most common driver mutation, in about half of melanomas. And now we’re finding there are other tumor types where you do find these BRAF V600E mutations. And there’s now a pan-tumor approval for dabrafenib/trametinib, it’s the combination of a BRAF inhibitor plus a MEK inhibitor, and certainly something we use for cholangiocarcinoma.

I actually have a patient where we used it in the front-line setting. A very unusual situation. But the patient was a professional piano player and was terrified of the toxicity from cisplatin, and so we actually got approval for it in the front-line setting.

DR LOVE: Wow.

DR YARCHOAN: Very unusual situation. But normally, again, these are things we’re reaching for after patients have gone through the front-line treatment.

DR LOVE: Interesting, though, he had metastatic disease and still concerned about acute issues. That’s very interesting. Did he respond?

DR YARCHOAN: He’s still on therapy doing well, yeah, with it.

DR LOVE: So I want to thank the faculty. Thank you for coming. Come on back at noon. You will not regret coming here at 12:15. Thank you.