Immunotherapy for patients with biliary tract cancers (BTCs)

DR LOVE: So my brain is full of EGFR right now because we did a program with Dr Neal on EGFR in lung cancer. And I was thinking about that when you were going through the TOPAZ data looking at durvalumab in first line therapy. Before I ask you about kind of how you interpret the trial globally, one of the things I was sort of thinking about, because one of the things we were talking about is the issue of IOs in people with targetable mutations. And the lung cancer people feel there’s data to suggest it doesn’t work as well. So I was curious, in the TOPAZ study, did they look at — did they do NGS or anything on these patients to see whether they had mutations?

I don’t know if they had enough people to see if there was a relationship to benefit.

PROF VALLE: Yes. So the answer is yes, but the data is not ready yet. So the study was presented earlier this year. A lot of the correlative studies are now going to be coming through. But the tissue has been collected to be able to understand exactly that question. So we will know, but we don’t yet.

DR LOVE: Any sort of guesses on what they’re going to see? Is there data on that up to this point? Any clues?

PROF VALLE: Yeah. I think there is a sense that maybe if there is a single alteration that those patients may be less responsive to immunotherapy. That needs to be tested and needs to be confirmed, so we don’t know that for sure at the moment.

DR LOVE: So the other thing, of course, is the clinical implications. Are people going to go ahead? And are you, if you could? Let’s put aside regulatory issues. That’s another question. But would you give durvalumab? It kind of looks like the benefit is fairly modest. I don’t know. For some reason, I was flashing on extensive stage small cell where when they add in an IO, you get some benefit. Everybody does it, but they’re not that excited about it. Is that kind of your feeling, that people are going to do it, but maybe it’s not all that great?

PROF VALLE: I think one of the challenges, and it’s not limited to the TOPAZ study, is to be able to identify who are the patients who are actually deriving the most benefit.
If you look at the study in its totality, it is an incremental step. If you look at the median, it’s not so impressive. If you’re looking at the 2-year survival, that is really, you know, a 15% difference at 2 years is clinically very meaningful.

So like with other IO studies, we want to really understand who is that 1 in 4 patients who is deriving that long-term benefit. I think, would we use it for all patients in my clinic? If I had access to it, I’d be very keen to do so, largely because of that separation of the curves which is a divergent curve. They don’t come together again. And there’s that real tail to the curve which we need to understand.

DR LOVE: So, of course, the usual question that comes up is looking for or trying to identify who is going to benefit is PD-1 and TMB and other markers. Anything there?

PROF VALLE: So that has been looked into. There was an assessment of PD-1 expression in the TOPAZ study and it looks in these plurality subgroups that did not predict for benefit. You may recall that we’re not able to predict benefit either in hepatocellular carcinoma. So it looks like there’s no simple biomarker that’s going to predict for benefit or even lack of benefit at the moment that we’ve identified so far.

DR LOVE: Any data with anti-CTLA-4 in PD-1?

PROF VALLE: So at the moment there are some combinations of checkpoint inhibitors using dual combinations. The pivotal study by Dr Oh et al performed in Korea did show very high response rates, but there was also that incremental addition of toxicity. And, in fact, the magnitude of efficacy favored the addition of single in terms of durvalumab rather than the combination of durva with tremelimumab.

Etiology and presentation of and recent advances in the management of cholangiocarcinoma

DR LOVE: So you mentioned a correlation with hepatitis which I wasn’t aware of. I had jotted down when you mentioned that I was going to ask you about something that I hear people talking about, but I don’t know much about like the idea of a mixed HCC/cholangio type picture. Is that an entity? And what do you think is going on there?

PROF VALLE: Yeah. So 2 things here. In fact, we know of the well-established link between cirrhosis from whatever etiology in hepatocellular carcinoma. In fact, we’re increasingly aware now that cirrhosis, again, from whatever etiology, does also increase the risk of cholangiocarcinoma. It’s probably been under-reported. And, in fact, Dr Edeline in France is currently leading on looking at this in more detail so that we can try and quantify what the prevalence of underlying cirrhosis is in patients with cholangiocarcinoma.

The second point is about the mixed tumors. Mixed tumors are indeed a thing and there’s a lot of discussion around the cell of origin. And one of the difficulties is that these patients are usually excluded from the HCC studies and they’ve also been excluded from the cholangiocarcinoma studies. So they’re a rare group who are often excluded from studies. And I think it will probably be international collaboration where we’re pooling information around these patients in international datasets that will be able to help us understand them in more detail.

DR LOVE: So, again, before we get into the cases, one other thing that I was just sort of thinking about as you were going through, particularly at the beginning of your talk in terms of providing sort of an overview. I wonder just more, without the slides, just more maybe the way you might explain it on rounds, et cetera. You can talk about 2 things in terms of your more global vision of these diseases or this disease. One is sort of the clinical presentation and the clinical course of these various, you know, entities, palliative issues, et cetera, management issues. It sounds like in the metastatic setting, things kind of come together in generally. And then, your view kind of biologically of these diseases when you think about the epidemiology, what we know about alterations. Again, particularly for the point of view of a clinician who is looking for stuff that’s really going to help them take care of patients and understand where things are heading. Can you just sort of just chat a little bit about your vision of this disease or these diseases?

PROF VALLE: Yeah, thank you. My first observation is we’re late to the party. You’re looking at other cancers, breast cancer, lung cancer, where you’ve got many, many more treatments, you’ve got very well-established annotation of molecular alterations. Until 12 years ago, we didn’t even have a standard of care. And, in fact, most of the clinical trials when they were reporting just said these are too rare to be able to do any randomized studies. We now know that’s not true. What was missing was collaboration. Thankfully, now with collaboration, we are hopefully catching up and we’ve now got increasing numbers of standard of care in terms of treatments.

In terms of the clinical presentation, I think there are 2 quite different. And, again, my focus is on advanced disease. Patients with intrahepatic cholangiocarcinoma often present with very large tumors, 7, 8, 9, 10, 12 cm tumors, which have been picked up because of a blood test that’s shown very minimally deranged liver function tests or sometimes patients are then developing some symptoms like right upper quadrant pain. There’s usually a very big surprise that there is a tumor that’s that big. That usually also tells me that the tumor has been relatively slow-growing because, obviously, as you know, the liver itself doesn’t feel any pain, but the capsule around the liver if it becomes stretched, becomes very, very painful. So in order for something to get that big, it must have been stretching very slowly. Patients with perihilar and distal bile duct cholangiocarcinoma usually present with biliary obstruction. So the classical jaundice, of course, people will think initially gallstones. Is it pancreatic cancer? But then we find that the biliary obstruction is at the level of the hilum of the liver or in the distal bile duct. That follows a much more classical pathway of evaluating where the obstruction is and if operable, then using biliary stents to relieve the jaundice. Gallbladder cancer is much rarer. It’s unusual, but patients are sometimes found to have a gallbladder cancer when they’ve had a cholecystectomy for what’s considered to be benign disease. Those patients need to have completion surgery. But in patients who present with advanced gallbladder cancer, usually, it’s metastatic into the liver often disseminated into the peritoneum. So I think there’s quite a broad range there of presentations. Unfortunately, there’s no early warning except for patients maybe who’ve got a distal bile duct cholangiocarcinoma who may have a very small tumor. It causes obstructive jaundice. Everybody then knows where to look and they can have curative surgery.

Just to quickly give you a sense of where we’re going. It has been an exciting 2 or 3 years, maybe 5 years, in biliary tract cancer. There are large groups that have been undertaking molecular profiling, predominantly in surgical series. And so we know a bit about the surgical series. We know that the disease in Thailand which is liver fluke related has a different signature, more likely to have KRAS TP53 mutations. But the identification of these subgroups for which there are therapies is very exciting. It really has changed the management of these patients. So somebody comes to me now with a cholangiocarcinoma, the question is what’s the molecular status of this patient?

DR LOVE: And incidentally, a couple of years ago, I probably wasn’t the only person to come up with this, but I remember saying it’s starting to look like cholangiocarcinoma is the new non-small cell lung cancer. Do you buy into that one?

PROF VALLE: I completely buy into that. I think in terms of the GI cancers, it’s becoming one of the most targetable ones, depending on where you put your cut-off. But it looks like approximately 50% of patients may have a targetable alteration.

DR LOVE: I was going to ask you that. 50% of patients?

PROF VALLE: Yeah.

DR LOVE: Are you like including KRAS in that?

PROF VALLE: Well G12C. So like I said, there’s only 3%, but once you start adding all these very small slices of the pie, they do add up.

DR LOVE: So I want to go through that with you and, of course, the approved strategies, but as long as you brought up KRAS, I’m just kind of curious. Of course, we talk about that a lot, particularly in lung cancer. And also, I was curious, I think, there is a paper, I think it was in pancreas, of CAR T or some kind of T-cell thing in KRAS G12D where they saw a response in a patient. Just out of curiosity, is CAR T something that maybe you think could be looked at in cholangio?

PROF VALLE: Yeah, I think the important thing here is being able to find the right target which is the driver mutation for that particular cancer. And we know that this is possible. One of the patient advocates for the Cholangiocarcinoma Foundation had this therapy and has done extremely well.

DR LOVE: Really?

PROF VALLE: Is a poster child for cholangiocarcinoma.

DR LOVE: CAR T?

PROF VALLE: Yes.

DR LOVE: Really? Wow. This is real CAR T?

PROF VALLE: It’s real CAR T. Yeah. It’s real CAR T.

DR LOVE: Okay. Okay, got it.

PROF VALLE: It was targeting a molecular alteration that was identified in that particular tumor.

DR LOVE: Oh, really? That’s really interesting.

Targeting FGFR alterations in cholangiocarcinoma and other BTCs

DR LOVE: Anyhow. As long as I asked you about that, maybe you can just comment on what you went through in your lecture. Again, where are we today? What do we know about some of the newer drugs, sotorasib, et cetera, adagrasib, in cholangio?

PROF VALLE: So this is where the data is very new and still evolving. What we’ve seen from the recent CRYSTAL1 study is just that proof of principle that if we’re able to find the alteration in non-pancreatic patients including the biliary tract patients, we can get a 50% response rate. We’re not even seeing that with chemotherapy. Our standard of care, cisplatin and gemcitabine chemotherapy, gives us response rates in the region of 25%. So this is really very impressive.

DR LOVE: So let’s start out with the targeted therapy that is approved right now. Maybe you can begin with FGFR. We showed a video at ASCO of this doc in practice going, I just don’t understand FGFR. What’s the difference between FGFR1, 2, fusions, mutations, et cetera? You went through that very well in your talk with slides. Maybe you can just sort of chat a little bit about what these kinds of FGFR alterations are. You were talking about particularly fusions. And then, maybe we can kind of get a little bit into what we know about targeted therapy. What fraction of people have alterations related to FGFR?

PROF VALLE: Yeah. So with FGFR, the one that’s really relevant for intrahepatic cholangiocarcinoma are the FGFR2 fusions. And the fusion can have a number of different partners. The commonest one by far is the BICC2 fusion. But, in fact, there are a number of others. And, in fact, there is a long tail of any cause one in terms of cases reported of fusions. So it appears that the partner doesn’t really matter so much as having the fusion itself. So we know from the early work from the FGFR studies that, in fact, patients who don’t have FGFR2 fusions or have different alterations like mutations do not derive the same benefit as patients with FGFR2 fusions. So the key message is for patients with cholangiocarcinoma is identifying patients with FGFR2 fusions.

DR LOVE: What fraction of patients have that?

PROF VALLE: So that’s a very relevant question because initially, we thought it was around 20 to 25% of cases. It looks like that’s a bit on the high side and the truer figure is probably in the region of around 9 to 10%. The reason for that is that the first figure will have come from high-volume centers where these patients who may do better will seek second opinions and therefore have enriched for that population. If we look for a completely unselected population, and there’s a very nice paper published recently, has shown that this is more in the region of 9 to 10%.

DR LOVE: So for those patients, can you talk a little bit about the available agents that have been studied, what we know about the agents and what the difference is between, you went through multiple FGFR inhibitors?

PROF VALLE: Okay. So we’ll quickly talk about what’s currently approved. So we have pemigatinib and infigratinib. Both of those are approved in the US by the FDA. In Europe, pemigatinib is approved. We don’t have any others to date. Both pemigatinib and infigratinib are ATP binding compounds. The newer generation called futibatinib is a covalently binding compound which is irreversible. And so it appears to be that the activity of futibatinib may be enhanced by that covalent binding. We’ve also been seeing some evidence coming through for futibatinib in patients who have previously received treatment with pemigatinib. So looking, again, to look at patients with resistance to pemigatinib. Some of the in vitro work as well as some of the work coming from Mass General from Dr Goyal’s group has shown that futibatinib can overcome some of those resistant mutations.

DR LOVE: That is really interesting. My macro mind, I’m just trying to take in all the stuff I hear every day. When I hear covalent and noncovalent, I know it’s completely irrelevant, but the first thing I thought about was CLL with BTK inhibitors.

And, again, they see responses, lots of responses in people who progress on the first line. So I don’t know why the covalence or noncovalence makes that much difference.

PROF VALLE: Yeah, I think it’s the fact that when it’s covalently bound, it’s irreversible. So you think of an irreversible blockade. And I think what we need to understand going forward is whether we should be starting with those compounds or whether we should be using them in the setting of disease progression after a frontline or an earlier FGFR2 inhibitor.

Just to quickly finish off, there are some clinical trials. In fact, there are 3 global studies that are now comparing an FGFR inhibitor against chemotherapy, so bringing it into the frontline setting rather than the post-chemotherapy setting. Those studies are still recruiting, so there’s no readout yet.

DR LOVE: Yeah, I was going to ask you about first line because, again, when you think about, I guess, the grandparent here, non-small cell lung cancer, initially, they did randomized studies, chemo versus targeted, then they stopped when they saw a response rate of 60%. They just bring stuff into first line. I don’t know if that’s — right now when you look at it indirectly, does it look like maybe patients would be better off starting with this strategy or chemo?

PROF VALLE: So the evidence so far would suggest that we start with chemotherapy and use FGFR inhibitors second line. That’s where we have the data. That’s where the evidence base is. And so we would very strongly encourage clinicians and their patients to support the clinical trials which are answering exactly that question. In reality though, it’s likely that patients are going to receive both treatments because in the setting of disease progression, it’s likely that patients would then go on to have chemotherapy. So it’s nice to have some more lines of treatment for these patients, but the clinical studies really should be supported.

Spectrum and management of toxicities associated with FGFR inhibitors

DR LOVE: Yeah, that’s for sure. But oncologists are out there and they’re hearing all this stuff from the lung cancer people and they want to give it first line. Totally, you need the data, but I am curious though if you consider not only response rate, time to response, but also toxicity. Indirectly, how do those two look?

PROF VALLE: Well the toxicities are completely different. We’re comparing apples and pears here. And so I think it’s fair to say that the toxicities are fewer and different to the chemotherapy.

DR LOVE: Fewer and different or fewer and also better tolerated, quality of life-wise? I mean, cisplatin and chemotherapy here.

PROF VALLE: Yeah, but it’s cisplatin at 25 mg/m2. It’s low dose cisplatin. It’s not the high dose, highly emetogenic cisplatin. So this is a fractionated cisplatin which is a very well tolerated 2-hour infusion. So, for example, what we’re seeing with some of the FGFR inhibitors is nail toxicity. Now we might say well, that’s not so important for us as an oncologist, but for some of the patients, nail toxicity is really very troublesome. They’re very painful. And when you lose your nails, that’s very painful. And with longer term follow-up, we’re now seeing that patients are developing cataracts and need to have surgery for cataracts. So we are generating a new generation of adverse events which will have an impact on patient’s quality of life. So they are different and we need to adapt to those.

DR LOVE: How about efficacy roughly, response rate, duration of response, et cetera?

PROF VALLE: Yeah. So one of the things that we’re seeing with efficacy from some of the studies, remember that the studies included patients who had prior chemotherapy, but some will have received treatment in second or third line. And, in fact, it appears to be that the magnitude of response is consistent whether patients receive it in second or third line. So maybe the line of therapy doesn’t matter. I think what’s important though to remember is the performance status of these patients often deteriorates over time and the ability to give treatment will also decrease because of that. So it’s about making sure that we’ve got the best available treatments first. I think it’s likely that if the studies are positive, we’ll be able to use FGFR inhibitors in a first line setting. But, obviously, that’s speculative at this stage.

DR LOVE: So I’m going to bring in another thing, again macro perspective from a general medical oncologist, I’m not exactly sure how relevant it is. I don’t even know if it’s being studied in cholangiocarcinoma, which is erdafitinib. Which, of course, we hear about all the time in bladder cancer. So, A, has it been studied in cholangio? Is it the same type of fusion? And, of course, we hear a lot about toxicity. It kind of sounds similar to what we’re hearing about with these agents with the phosphate, et cetera. But what about erdafitinib?

PROF VALLE: So there are studies using erdafitinib. There are others that have also not yet got any names behind them. They’re just alphabet soup from different companies. There’s a string of second and third generation FGFR inhibitors. I think one of the things that we’re looking for as clinicians is something that will improve some of the toxicity profile. We know that the mechanism of action may mean that FGFR inhibitors can be derived that don’t cause problems with hyperphosphatemia. And that, of course, would be something that would be welcome by clinicians. So we are looking to some of these compounds being developed and come through to the clinic.

DR LOVE: So let’s talk a little bit about the hyperphosphatemia. Again, I asked the GU people about this trying to figure out to use phosphate lowering drugs. How big of a problem is it? What’s your perspective having used these drugs, both clinically as well as in clinical trials? What do you see with the phosphate? How often do you see the problem? When does it start? How much of a problem is it? What do you do about it?

PROF VALLE: Yeah. So we see a problem usually in around one-third to half of patients, so it’s not every patient. Because the studies had already identified that problem, there were very clear and strict guidelines on what to do with phosphate. So when patients were about to start treatment with FGFR inhibitors, we had a discussion about having lower phosphate in their diet, dairy products, meat, other protein containing foods. Not every patient needed to have phosphate lowering therapies. But, again, we did need to instigate this in some patients. Probably only half of those actually did develop an elevated phosphate. So it was very manageable. Did we have to interrupt treatment or discontinue treatment completely for patients due to high phosphate? No. We were able to manage that through.

DR LOVE: What are the clinical sequalae of high phosphate? What kind of clinical problems can you get into if it’s not controlled?

PROF VALLE: Think of it as a high calcium. So you can get stones and things like that.

DR LOVE: Really?

PROF VALLE: And so you get deposition of phosphate crystals in the wrong places.

DR LOVE: So we’re actually about to do a CME program on onco-ophthalmology because there’s so many drugs now, mainly antibody drug conjugates, with eye issues. But on example is these FGFR agents, again, including erdafitinib. I’m still trying to figure out all these different eye things that happen. You were mentioning about cataracts. What you hear with erdafitinib is central serous retinopathy and other stuff. What about the FGFR inhibitors that you were talking about here, pemigatinib, infigratinib, futibatinib?

PROF VALLE: Yeah. So clinically, we’ve not come across many problems. Patients have obviously been referred and they’ve had their eye assessments. And I cannot recall a patient where we’ve had to change or interrupt the treatment because of anything that we’ve seen on the ophthalmological assessments. But we have had patients who needed to have cataract surgery. Now it’s always difficult to know to what degree there was a background cataract to start with and that has been exacerbated or accelerated. But we have had that in some of our patients.

DR LOVE: Any of these symptomatic in terms of vision or dry eyes or any symptoms the patient has?

PROF VALLE: Yeah. Dry eyes, but not particularly troublesome for patients. So from my point of view, it’s mainly been some of the GI toxicity and the nail toxicity that’s actually been more pressing.

DR LOVE: Right. The nails. Yeah, we’ve heard about that. And you have this great slide you showed with 4 waterfall plots that all look pretty similar, 3 of them pemigatinib, infigratinib and futibatinib, but the last one, derazantinib. Is that one of the others, so to speak?

PROF VALLE: That’s also ATP bound from my recollection. And, in fact, that was one of the earlier studies to report, Mazzaferro and colleagues.

DR LOVE: What about the differential? You mentioned the, it sounds like encouraging, finding there with futibatinib with responses after prior. But when you look at these globally, is there a difference in tolerability? Like do you see more toxicity with futibatinib?

PROF VALLE: I have to say, it’s very difficult to put a card between them. The toxicities that we’re seeing really do appear to be a class effect and something that we’re getting increasingly familiar with managing. Like I say, if we are able to get an inhibitor into the clinic which would get rid of some of the phosphoremia, that would be differentiating. The other thing I guess is that we are seeing different absolute response rates. I think we have to be very careful when we’re comparing between studies because, obviously, the patients are going to be slightly different in terms of their eligibility, prior therapy, performance status, labs, et cetera. So I think in general what we’re seeing are very encouraging response rates, more than we see with chemotherapy. We’re seeing responses which are durable, and that’s important. And patients are deriving good quality of life whilst on treatment.

Targeting driver mutations beyond FGFR

DR LOVE: So you also talked about IDH inhibitors, specifically IDH1. Again, can you comment on what we know in terms of efficacy, tolerability, and what about IDH2?

PROF VALLE: Okay. So what we’re seeing with IDH1 is actually different to the FGFR inhibitors in that we’re not seeing the big response rates. The response rates are in the region of around 5% of patients. So it seems to be more of a cytostatic effect, whether that’s to do with the mechanism of action by targeting the oncometabolite, 2-HG. So really, when we’re looking and interpreting the data of the IDH1 inhibitors, we’re looking for disease stability rather than response. And that’s obviously reflected in the progression free survival Kaplan Meier curves that you saw. One of the things we’re also learning about IDH1 inhibition is that isoforms switching to IDH2 may be one of the escape mechanisms. So there is a lot of interest at the moment around IDH2 inhibitors or combined IDH1 and IDH2 inhibitors. We don’t have enough data at the moment to know whether that’s the right way to go, but that’s an active area of investigation at the moment.

DR LOVE: Incidentally, of course, we talk about IDH inhibitors all the time in our AML programs but, of course, one of the things they talk about there is differentiation syndrome. Obviously, that’s not going to be exactly what happened in another cancer, but I don’t know. Is that type of process, you think it goes on with the cholangio, it’s just not clinically evident?

PROF VALLE: Yeah, you’re right. It’s very difficult to detect that clinically although there has been a nice paper published that was looking at the degree of differentiation as well as the Ki-67 and was able to demonstrate that, in fact, as a result of IDH1 inhibition, there was improved differentiation. There was a reduction in the Ki-67. So obviously, in the clinic, it’s very difficult. It’s very different to leukemia where you can make that assessment much more easily.

DR LOVE: So I was going to ask you about MSI although it kind of looks like it fits into what you would expect which is if they have it, they’re going to respond to a checkpoint inhibitor pretty much the same way as colon cancer and that you need to look for it even though it’s not very common. That’s the message that goes out in general in solid tumors, particularly adenocarcinomas. But the thing that I was going to ask you about, because I was thinking about the tumor agnostic indication in MSI-high, you were also talking about BRAF — anti-BRAF therapy, dabrafenib/trametinib. And, in fact, I think in the last couple days, again, we saw a non-tumor-specific indication for dabrafenib/trametinib. So I was going to ask you whether or not it works. And I guess it looks like on the waterfall plot, it does work. And I guess you can give it, right?

PROF VALLE: Yeah. So in the UK, unfortunately, we don’t have access to it yet. But I think the point that you are making is that we’re now thinking about cancer more as kind of agnostic groups with identified molecular drivers. And, of course, the more we’re able to do some of this sequencing, we will identify some of these groups. Now not in every case do you find a driver mutation, but if there is a driver mutation, then you can get very good effective treatment. I think increasingly, the way I see things going in the future, that we are going to identify these groups through kind of basket studies and we’re going to go for agnostic indications much like NTRK and other fusions, for example, that have come through to treat regardless of the anatomical site of primary.

DR LOVE: Incidentally, have you seen any patients with NTRK?

PROF VALLE: No. We’re looking. We haven’t found one yet.

DR LOVE: That’s what the lung people say all the time. And the other day, we presented 2 cases from the same general medical oncologist with NTRK.

PROF VALLE: Wow.

DR LOVE: Anyhow.

PROF VALLE: Won the lottery twice.

DR LOVE: Actually, when I look at all the things that you were talking about, so much hope for the future, particularly targeted therapy, IOs are coming in. But I think one of the most exciting things you talked about in your talk was at the end when you were talking about HER2. It’s not about pertuzumab and trastuzumab either, it’s about T-DXd and what they presented there and, of course, you can imagine, we’re talking about that all the time, not just in breast, but lung and GI, et cetera. We, of course, just had the HER2-low presentation which really has, of course, a huge, huge study in breast cancer. Of course, the other cancers are also wondering what the deal is going to be there. And then you presented data, again, kind of familiar looking waterfall plot. It looks like most of these patients are going down. There are not that many of them, but it looks like it works pretty well. Have you ever used it, incidentally, in a patient with cholangio?

PROF VALLE: No. So this is something that really is breaking. And the data, as I understand, is limited to the Japanese dataset, I think.

DR LOVE: So I guess, again, it at least looks exciting. You’re seeing responses.
It sounds like kind of what’s being seen with the other cancers. But also, of course, the issue is interstitial lung disease. And it looks like they saw that as well. And, of course, everybody is thinking about that. It kind of seems like as time is going on that maybe they’re getting more of a handle on it in terms of keeping an eye on people’s CAT scans, et cetera. Any thoughts about where you see this agent heading? And the other thing is how often do you see overexpression, amplification? But also, at ASCO, they were talking about HER2 mutations, what you see in lung cancer. Do you see that in cholangio?

PROF VALLE: Yeah. So we do see mutations in cholangio although at the moment, they’ve largely been excluded from the HER2 studies which are predominantly focusing on amplification. I think one of the themes here is about drug-induced lung injury, we’ve learned a lot from treatments, for example, in my other field of everolimus looking at everolimus-induced pneumonitis. And, in fact, the more we use these agents, the more we’re seeing these early changes on CT scans from which patients are often asymptomatic. But we now know that we need to get on it. We need to interrupt the treatment, use steroids, for example, to get things under control. We can then rechallenge once things are resolved. So I think as we get increasingly familiar with some of these compounds, we’re going to look for these toxicities and be able to handle them and hopefully be able to continue the treatment.

DR LOVE: Yeah, I had a general medical oncologist the other day who was presenting cases to me and we were talking about T-DXd and he goes, oh yeah, I used it in this patient with endometrial cancer and the patient had a complete response. And I’m like, I didn’t even know endometrial cancer was HER2 positive. But I guess we’re going to, you know, it’s going to be, I think, increasingly tempting in the other cancers if you see HER2.

PROF VALLE: Absolutely. Yeah, absolutely.

DR LOVE: We’ll see where that heads. Well let’s finish off and just chat a little bit about your cases here.

Case: A man in his early 60s with intrahepatic cholangiocarcinoma, an FGFR2 fusion and an IDH1 R132C mutation

DR LOVE: Can you talk a little bit about this 60-year-old man?

PROF VALLE: Yeah. So the first case was a 60-year-old male who underwent a right hemi-hepatectomy for intrahepatic cholangiocarcinoma confirmed to be a moderately differentiated adenocarcinoma. Unfortunately, at the time of surgery, the surgeons felt that it actually macroscopically had gone through the tumor and this was confirmed pathologically. So it was, in fact, an R2 resection. That doesn’t happen very often. Normally, the surgeons will not take a patient to theater if they think it’s going to be an R2 resection. So knowing that there was residual disease, that patient went on to have cisplatin and gemcitabine chemotherapy. This story starts off 5 years ago. At the end of treatment, the patient’s scans showed no visible disease. But, unfortunately, around 9 months later, there were new liver lesions as well as distant lymph nodes. And the patient was rechallenged with cisplatin and gemcitabine. But while they were receiving that treatment, they underwent molecular profiling. Intriguingly, they were found to have both an FGR fusion and an IDH1 mutation. Now I have to say, we’ve thought of these as mutually exclusive aberrations. There is a small number of cases where we are seeing both FGFR2 fusions and IDH1 mutations. And, of course, the question is in 2022 or maybe 2023, what’s the preferred inhibitor?

Once the patient had progressed, in fact, we didn’t have any standard of care treatment. And so the patient was enrolled in the futibatinib study using TAS-120 as the name previously was. This was part of the clinical trial. The patient did develop hyperphosphatemia. And I’ve shown on the slide the phosphate levels which you can see were more troublesome at the beginning. But we then managed to control that keep it within the normal range. When the patient discontinued futibatinib, it was no longer a problem. So it was very much related to the treatment. The patient went on to have a partial response by RECIST with 33% reduction in the measurable lesions. And the best response, in fact, was just over a year from starting treatment. He had problems with nail changes and cataracts which we’ve discussed previously.

DR LOVE: So is he currently still on treatment?

PROF VALLE: No. The patient — sorry, I’m just showing here the scans. This was the baseline progression scan, then the best response scan which is focused on one particular lesion in the liver. And then on the far right, you can see that when the patient did progress, there was a necrotic center to the lesion, but a very active rim of tumor which was also compatible with lymph node progression elsewhere. So the patient went on to have chemotherapy with FOLFOX. So we’re now going on to kind of standard of care second line treatment. Remember, we don’t have access to ivosidenib. And, unfortunately, he developed an occipital infarct, we think, from the chemotherapy, predominantly the platinum element. So once the patient recovered, we switched his chemotherapy to FOLFIRI and he’s currently on that. But this patient is alive 5 years after his initial diagnosis which in biliary tract cancer is notable. When he has disease progression, of course, we’d like to consider ivosidenib. It’s not yet available in Europe. It is approved in the US. But that is somewhere we’d like to go with him.

DR LOVE: When he was started on the futibatinib, was anything done — do you do anything today preemptively to deal with phosphate? Do you change their diet? Do you give them phosphate binders? Or do you just sort of wait?

PROF VALLE: Now we do give them the dietary advice to go on a low phosphate diet. We don’t start the phosphate binders. We do that in response to the phosphate levels. So if the diet is not enough to control it, then we introduce the binders.

DR LOVE: And in this patient, when you think about the entire course there on futibatinib, how would you characterize quality of life? Was the patient able to work or engage in normal activities? Were there any chronic symptoms that were a problem?

PROF VALLE: Yeah, the main problem that this patient had was, in fact, oral mucositis. Just to say, these toxicities have all been reported as part of the clinical trial. So there’s nothing that hasn’t been reported. He had recurrent mucositis with mouth ulcers. And for him, that was the main problem. It required interruption, particularly once he’d been on treatment for a long period of time, we needed to interrupt his treatment. The ulceration would improve and as soon as we restarted again, we then had a recurrence of the ulcers. So we kept on going in blocks of treatment where we then would allow his oral mucositis to improve. They didn’t look like hepatic ulcers. We did cover for that on one occasion, but that didn’t seem to make a difference. And, in fact, once he completed the futibatinib because of disease progression, thankfully, his oral mucositis completely resolved. But like I said, this did impact on his quality of life, but he was desperate to remain on the treatment. So it was this tension between treatment is working for me, but is impacting on my quality of life. But he was able to be on treatment for 15 months.

Case: A woman in her early 60s with intrahepatic cholangiocarcinoma and an IDH1 mutation that did not respond to third-line ivosidenib

DR LOVE: Interesting. How about this 62-year-old woman?

PROF VALLE: So a 62-year-old female was also somebody who had hepatectomy for intrahepatic cholangiocarcinoma. It was a pT2a tumor. Unfortunately, she relapsed. This was at a referring center, so she did not receive any adjuvant treatment. To that point, it wasn’t established as standard of care. Unfortunately, she relapsed just under a year later with additional disease along the surgical margin. It was deemed to be resectable, but the biology was thought to be unfavorable because she’d relapsed in a relatively short period of time. So locally, she had received chemotherapy with cisplatin and gemcitabine with review to surgery which she then did have. She had a laparotomy. But unfortunately, at the time of surgery, she was found to have inoperable disease because of vascular involvement which hadn’t been seen on her preoperative imaging. So at that point, she was referred to our institution. She was referred for consideration of radioembolization because she didn’t want to consider chemotherapy.

She was deemed to be suitable for radioembolization which she received. And she then had surveillance imaging which showed a minor response after 3 months, after 6 months. But then unfortunately, after 9 months, she was found to have new pulmonary metastases in keeping with extrahepatic disease progression. At that point, she gave consent for her tumor to be molecular profiled within a clinical trial. Unfortunately, there were technical issues. There was not so much — there was not sufficient tissue and it failed. The patient at that point declined a further biopsy and we were unable to persuade her on the importance of understanding the molecular profile. So she received chemotherapy. And then while she was having chemotherapy, she consented to have a biopsy. And, in fact, that identified an IDH1 mutation.

So she stopped chemotherapy after 10 cycles of FOLFOX and we then switched her to ivosidenib as part of the clinical trial. Unfortunately, she didn’t derive benefit from ivosidenib. So as we know, not every patient is going to derive benefit even if they do have the molecular alteration. A scan at 6 weeks had shown some increase in size of her measurable lesions by 19%. According to the protocol, that was stable disease. We kept her on the clinical trial. But her next CT scan did confirm disease progression, 34% increase by RECIST. And she therefore discontinued. And that disease progression was in keeping with a rising tumor marker, her CA 19-9 was increasingly rising as the scan showed progression.

She then went on to have cisplatin and gemcitabine rechallenge. And her CA 19-9 did respond to treatment. And she also had radiotherapy to a sternal metastasis. Unfortunately, her performance status started to deteriorate. A CT scan showed disease progression. So although there was an improvement in the tumor marker, it was short-lived and then it started rising again. And, unfortunately, the patient died soon after choosing to go on best supportive care.

DR LOVE: I was going to say did she have any tolerability issues with the ivosidenib? Do you generally see any tolerability issues?

PROF VALLE: Yeah, not at all. And remember, within the ClarIDHy study, which is the study that was published, we didn’t know whether she was receiving ivosidenib or placebo. So it was double-blinded. And, in fact, when she did progress, she was unblinded. We thought she’d been on placebo because there was really no tolerability issues at all. And, in fact, she had been on active drug.

DR LOVE: Wow.

PROF VALLE: So we were disappointed. We were hoping that she’d been on placebo and could then be switched over, but unfortunately, that was not the case. I think it just highlights that whilst identifying an IDH1 mutation means that patients have a chance of having disease control due to ivosidenib, it doesn’t happen in all cases.

Case: A woman in her early 60s with gallbladder cancer who received first-line chemotherapy with pembrolizumab 

DR LOVE: All right. How about this last patient, this 63-year-old woman?

PROF VALLE: Yeah. And our last case is somebody who, in fact, has a gallbladder cancer. She had an elective cholecystectomy 4 years ago. She is still alive at the moment. In the cholecystectomy specimen, she was found to have a moderately differentiated adenocarcinoma, pT2. So she then went on to have completion surgery, which is what the standard of care would be, to remove the gallbladder bed as well as the adjacent liver. And, in fact, although there was no residual disease in the gallbladder bed, 1 out of 5 lymph nodes was involved with adenocarcinoma. So she went on to receive adjuvant chemotherapy based on the BILCAP study results for about 6 months and finished that. And then just under a year later, a surveillance CT scan showed a suspicious focal lesion in the left lobe of the liver. FDG scan confirmed that that was recurrent disease together with additional nodal disease at the porta hepatis as well as distant lymph nodes.

So this lady, in fact, was enrolled in a clinical trial that was looking at the combination of cisplatin, gemcitabine and pembrolizumab. So this is, of course, a checkpoint inhibitor, but different to the one used in the TOPAZ study which used durvalumab. Pembrolizumab has been used in the KEYNOTE-966 study. We’re awaiting the results of that study which will complement the results of TOPAZ. But the study that she was in was a single arm Phase II study using pembrolizumab in combination with cisplatin and gemcitabine. She had a partial response within 4 cycles of treatment with a 41% reduction of marker lesions. In fact, by the time she’d had 16 cycles of treatment, she’d had a 69% reduction in her measurable lesions. We’d had to take out the cisplatin due to neuropathy. And she also had a nice CA 19-9 response. However, we then saw that her CA 19-9 started rising which was obviously suggestive of disease progression.

I’ve shown here the response that she had in her target lesion in the liver which you can see between the scan of September ’20 and a year later has completely disappeared or certainly can’t be seen by the radiologist. But based on the rising tumor marker, CT and PET scan unfortunately did confirm that she had progressive disease. And this was confirmed as she was on immunotherapy, the protocol driven assessments meant that we continue treatment and had to have confirmed progression and that was indeed confirmed.

At that point, we offered her second line chemotherapy. She was willing to start FOLFIRI, but we were then able to identify a clinical trial slot for her. I’m sorry, I’m not able to share exactly which compound that is because the study is still ongoing. But the patient has had a very nice CA 19-9 response as well as a radiological response and remains on study. But I guess the question is now where do we go for in third line when she does progress? Because that’s what question she keeps asking. We would, based on the NIFTY data, consider FOLFIRI using standard irinotecan. The NIFTY data, just to remind you, used nanoliposomal irinotecan rather than conventional irinotecan. We don’t know what the incremental benefit would be from the nanoliposomal element, but we would use FOLFIRI chemotherapy for her.

DR LOVE: Could you tell us the class of the drug that was studied?

PROF VALLE: Yes. It’s a WNT pathway inhibitor.

DR LOVE: Wow. That’s interesting. It sounds like it might be promising.