How to Treat Biliary Tract Cancer – Treatment Algorithm with Dr. Suneel Kamath

Hello everyone, welcome back to another episode of The Oncology Brothers. I'm Rahul Gossane and I'm Rohit Gossane and we're both community medical oncologist. Just like many of you listening out there, we are trying to keep up to date with this rapidly changing landscape. So we can all continue to provide the best care to our patients close to home. In today's episode, our focus is on biliary track cancer. Though this is not the most common cancer we see, but it does carry a poor prognosis overall. Rohit Gossane is a very important part of the recovery of the patients. The main goal of this is to get the best care to patients close to home. We're looking at the most important treatment for the patients close to home. And so I think I would still kind of think of keep sight of being as the main say of therapy for adjuvant therapy. But I would also add to I think this is definitely an important space for our IAR colleagues, for radiation oncology, involving Y90 and SBRT as well for those with multifocal disease. I mean, these are definitely patients that if you have a good response, can be downstaged and make it surgery or you're thinking about transplant for some of those cases, which you know, the past seem crazy, but is actually possible for for the select few people. So you know, thanks for getting us started. So you both have touched on this for early stage surgery for locally advanced multi-d approach ends up being very important. This is when we're relying on a radiation oncology or IAR colleagues. Okay, shifting gears to metastatic disease. This is where as medical oncologists, we're often taking the lead. In frontline settings, we have data from Topaz one study for James is Derva. And keynote 966 with Jim says, Pembro. Media and overall survival is very similar in both studies, roughly 12 and a half months. In Topaz one, we dropped chemotherapy after eight cycles, whereas in keynote 966, we continue with the chemotherapy part as well. So, what is your preferred option in frontline settings? As you as you mentioned, the most important thing about both of these regimens is that the overall survival data is extremely identical. It was kind of remarkable. I remember I think Topaz one, it was 12.5 and keynote 8 or 966. It was 12.6 maybe it was and the control arm slightly different. It was love point five and 10.8. It was very remarkable like how tight they were. So really, I would say it's kind of dealer's choice in my view. It's sort of what you're more comfortable with. What you tend to use more often in your practice. I think either is fine. I would definitely advocate for dropping the Jim site of being whichever way you attend to go. So unlike keynote 966 where the Jim site being was continued with the Pemberlism app, I would definitely advocate for dropping the chemo entirely both a gem and cysts beyond the six month mark. And really, I think that's the advantage with Topaz one as we have evidence showing that the continuation of the Jim site being really didn't make a bunch of an impact as we saw in keynote 966. I think that's really critical for metastatic and advanced setting, Kalantik, carcinoma is giving people that treatment break. You know, once you're on single agent immunotherapy, there are a few toxicity that's a good quality of life period and really helps people to be prepared then for second and third line therapy. And even for a practical standpoint, I find I run into a lot fewer sight opinions and GI toxicity. If you've given people that break, once you get to your full foxes and full theories of the second and third line, I think you're better able to stay on treatment and get better results out of those later regimens if you cut the chemo for a little while. Thanks for covering that, Sunil. Before we dive into the second line treatment options, which almost looks like lung at no carcinoma, given the targeted therapies that we have available here. What's taking to our frontline option here, Sunil, does it even matter to differentiate between intra-hapatical angiobersus extra-hapatical angiore, the treatment regimen or the paradigm is rather the same? Yeah, in the first line setting, I would say it's largely the same. I think once a lot of those differentiations definitely apply more to the resectables setting. Once you get to metastatic disease, I would largely use the same regimens you would for an intrapatic versus extra-hapatic. Certainly there'll be differences in terms of prognosis and complications you have to watch for, management wise, but regimen choice, I think it's mainly the same. If you bring up a good point because bilirotract cancer relumped this all together extra-intra-hapatic and even gobladder, you don't see that too frequently here, but outside US. That is high in prevalence as well. So, if the Gorge cisplatin presence here now, if one has deranged kidney functions or hearing impairment, can this be replaced by carboplatin in this setting, though we do do that in lung cancer settings? Yeah, the efficacy with that is a little bit diminished compared to cisplatin. So it does seem like cisplatin is important in particular in this disease. I have used both carboplatin or sometimes even oxali platin as well in this setting, exactly for the reason you brought up renal dysfunction, yeah, ototoxicity, other concerns that way, or patients who have really big problems with nausea vomiting that we can't manage, sometimes switching to a carbo or oxali can make a big difference in those cases. And also one can go with cisplatin split dosing as well with that deranged kidney function. I want to touch a bit on the MSI high disease story. For this particular entity, would you use chemo I/O combination versus I/O alone or rather dual checkpoint inhibitors? Yeah, that's a great question. I've been thinking a lot about that more these days as we're starting to see a smattering of MSI high tumors and other cancers outside colorectal. And I would still say, maybe this might be a little bit old school or conservative, but I would probably still go with the standard chemo immunotherapy in those cases. There's very limited evidence, largely in late-line settings for biliary tract cancers and immunotherapy. And I think MSI high, I think we love to think about it as this fully conquered disease, you just give I/O and you're going to be fine. And it's really not the case. I think even in checkmate, AHW for colorectal with ibionivo, certainly the outcomes are amazing, but if you look at that top right corner of those curves, there are a lot of people progressing still. I think that's even worse, really, in BTC, in pancreatic also. So I think how MSI high is MSI high? I do think the underlying histology does matter. So I certainly worry about those having more rapid progression if you do just the sole I/O approach in this disease. I think you do need that synergy with chemo and I/O in biliary tract cancer. Not at all, MSI high patients are the same and then keeping that bulk of the disease and deciding chemo I/O versus I/O alone. But here, what next if the disease was to progress? Coming back to that biomarker and NGS story that Rohev you alluded to, we have a few options if the disease is hurt too positive or if we have actionable mutations here. Let's start off with hurt too positive disease. The prevalence of this in gallbladder is higher, but a little less in extra and intrahepatic colorengia carcinoma. It is important to check these markers regardless because we have good available treatment options. We have Zany.Temab and TDXD. More recently, we've seen a lot of data around Zany.Temab for GEA and gastric adenocarcinoma as well in frontline settings. Sunil, for that hurt too driven disease, how do you pick one option over the other? What data do you have in hand for this? It's become an embarrassment of rich situation in this tumor type which is nice to say. It's not something we normally have that problem in 10 years ago. So as far as hurt too is concerned, these are the two practically available regimens TDXD or in her two and then Zany.Temab. There's certainly evidence for the my pathway regimen, Trestusemab, and Pertusemab.Temab and Tukatinib as well in this disease, although neither of those are approved. I tend to focus on Zany and TDXD. I think for both of them, it's kind of remarkable how similar the efficacy data are. Both have response rates in the 40 to 45% type of territory, survival outcomes, very similar kind of 18 to 20 months or so. Mostly single arm studies, but still I think a reasonable size for both trials. I would say I largely go off of toxicity. The key difference here is with TDXD, you are still essentially getting chemo therapy. It is an ADC, but DRUCs C-Can, you can hear the T-Can, right? It's a rena-t-can-ish, right? And so, certainly there's issues with cytopinias, GI toxicity, and then, of course, the very feared pneumonitis that you see in rare cases with T-DXD. Versus Xanidatimab as a single agent actually is pretty tolerable. So the grade 3, 4, AE rates in the study, I forget exactly, but it was 20, 30% territory. This continuation rate was close to 10-15 maybe, so it really was not, it was a very well-tolerated regimen. Really the biggest problem you see with Xanid, often, in conjunction with chemo is diarrhea. But as a single agent, interestingly, that really goes away. So the rates of that are much lower, severity is much less, much easier to manage. And so, just due to that tolerability, I tend to favor Xanidatimab a little bit more on its layer. Right, well, you started off with HER2 being a hot topic, especially after GI ASCO in 2016 with the presentation of Horizon GEA01, where Xanidatimab was presented. And again, there itself, too, it showed very impressive results. With regards to what you stated, Sunil, TDXD is an active agent and same thing for Xanid, but the side effect profile is quite different. And as you alluded to, TDXD is an ADC, but it has chemotherapy type of side effects. Cytopenia is nausea vomiting, alopecia is in not to forget that interstitial lung disease with Xanidatimab. And of course, has to worry about diarrhea. And as you concluded that one would consider Xanidatimab because of the better side effect profile, with similar efficacy as TDXD and rather consider TDXD at a later time. Actually, before we move on to other actionable mutations, Sunil, with regards to some clinical pearls for managing diarrhea for Xanidatimab or nausea vomiting and ILD with TDXD, if you could just highlight that. So for Xanidatimab, so I would say it's a single agent, as we'll be using it in BTC, at least as of now. I would just make sure that people have a little paramide available at home. As a single agent, it doesn't seem like prophylaxis is really needed up front. So I think in this disease, you're probably okay with just having it PRM. In conjunction with chemotherapy, like full fox or capox as we would do in gastric cancer, in a soft geol cancer, definitely there I would be a big advocate for prophylaxis with low paramide. In the trial, they used the 4 milligrams BID just for the first week. Now I would probably say in your non-trial, quote unquote, marathon runner, type patients that you see in clinical trials, in the real world for what we see in the office, I would definitely say, do at least that for longer, maybe even doing a 4 milligrams TID for low paramide possibly. And I probably wouldn't plan on stopping it unless people's symptoms are relatively well managed. And I think especially important to keep in mind in the upper GI tract space, these are patients that are coming in nutritionally very deplete, right? They're often conceptic, losing weight from dysphagia. So they really can't afford even a couple of weeks of severe diarrhea, not eating well, and dropping further weight with that. So I definitely think we got to be aggressive in the real world population for managing that aspect of things because, you know, longer you can stay on therapy, especially up front, better your outcomes are going to be. I promise I'll come back to BTC, but while we're talking about horizon, GE Acer one study, something to keep in mind, 5FU bolus was omitted there here in BTC, clearly, Xenodaptimavis and active agent, but other side effects to keep in mind with TDXD, nausea, when using TDXD, we have to have triple antimatic regimen up front because this is indeed chemotherapy. Okay, now back to other actionable mutations, FGFR or IDH1. How common are these and can you touch on our available options here? So I would say most exciting is the FGFR2 fusions. Majority of these are going to be in your intra hepatic, collanger carcinomas. You know, around 10 to 15, maybe 20% of patients will have those, but yes, a very good target, very active agents in this space. So really, I would say the main two that I think about the most are Fudibatinib and Pemigatinib. Both of them have slightly different selectivities for, so these are actually pan FGFR inhibitors, slightly different selectivities for each of them one through four. Interestingly, the response rates seem a little bit different. You know, Fudibatinib from response perspective seems a little bit more active. Response rates were low 40s there, whereas with Pemigatinib was about 35, 36%. But the survival data actually with both studies was very similar. You know, it was about 22 months or so in both studies. So I would say probably both are similarly active. Based on that response rate difference, I do tend to focus on Fudibatinib a little bit more than Pemigatinib, but I think you can't go wrong either way. I do think this is a space that's important to put your best foot forward first, because there's not a lot of activity with sequencing these. I mean, certainly I have done it in my practice if you've kind of burned through chemo. They're not really eligible for further chemotherapy. So I say, hey, why not try it? But I'm not seeing a lot of responses when you're trying a second FGFR 2 inhibitors. So you're probably better off using your best thing up front. For IDH1, that's again, probably something mostly prevalent in the intrapatic collanger carcinoma, but can be seen the other cases. We have EvoCidNib there. It's really the only approved agent for that. And this is definitely less active, but still I think a viable option, second or third line for people, mostly stability. The response rate with this is single digits, really. But you will see around 55% of people with disease stability still. Definitely valuable in the second life space in this disease. And yeah, I think a funny thing that I've seen in my own practice and heard from other colleagues is that you will have these rare patients that have very durable control with it. It's one or two percent of people, but I have a couple of patients that you are three, four years out. They will be able to hit widespread metastatic disease and not really responding much, but it's staying stable for a long period of time. They're feeling great, doing great. And so for that select case, these can really be a game changer. Absolutely. And anyone tuning in, one big takeaway here is bilirietract cancer is rare. Looking and testing for this comprehensive biomarker is very important. Sunil, what about that disease where we do not have any of these mutations for biomarkers? After affron chemo immunotherapy, we have limited options here. Can you briefly touch on outside trials? What options are you relying on? Yeah, definitely. Yeah, the second and third life space definitely is much more limited. So I would say, our standard for a long time has been full fox. I think there's also good evidence for full theory as well. I would actually say, in my practice, I tend to go with full theory a little bit more often actually, even though the guidelines say full foxes that preferred. There were a couple of studies that came out a few years ago. One was looking at full fox versus just best supportive care. I was one of the ABC trials in ABCO 6 it was. And then there was another study. It was actually the napoli regimen of five of you in like the zonal retentican versus five of you alone. It actually seemed like the data were pretty similar, but to me, the one that had an active comparator with five of you is a little bit more compelling as far as evidence is concerned. And so I tend to go with full theory, honestly, a little bit more often. The other advantage there is after platinum in the first line, as some people are having neuropathy or renal dysfunction going into second line, so you can kind of space that out and reserve your full fox for later. I say for most people, you're going to end up using both. Whatever you use second, you'll reuse the other one third or vice versa. It's kind of more of a matter of sequencing rather than which one. But yeah, unfortunately, I mean, we're not seeing great outcomes here. Survival is often six months or less. And it's definitely a space where we need more effective therapies. Right. I have to agree. We clearly need more treatment options here. We have covered quite a bit here, so Neil, but before we close, any final thoughts for our listeners? Yeah, I guess a couple of things I like to plug that we already touched on here. Definitely, first of all, I would definitely plug. Don't do five if you ball us in the advanced setting for patients. There was a really great study. I was an evaluation of the flat iron health data. Looking at bolus 5, it doesn't seem to make a difference in outcomes at all, especially those who are advanced disease. So definitely cut it out for everybody up front. So I'm glad you brought that up. The other thing I would plug to, which this is definitely kind of my own practice, I would say, is for gem cysts, I find a lot of people really struggle with the day one, day eight schedule. And so for a lot of my patients, I'm actually doing it on every other week schedule instead. At first, I was doing it as kind of a dose modification for people that are having troubled side-apenias. And it just was happening so often that I actually end up doing it up front for a lot of patients. And I can't say I've seen a difference in outcomes fortunately. So that's another thing I would plug to think about that. For us, the eclectic clinic, we see a lot of people traveling from really far. So it's very disappointing from them if they drove in two hours away, then their ANC is 700 and I can't treat them. And so I think from telepability perspective, logistics and everything, I think that's another thing I tend to do a lot in my practice. I'd have to agree with the five a few bullets, so I don't tend to utilize that, whether it's in any upper GI, colon or even here in advanced settings. We do need more targeted options. And we are seeing some exciting data from Keras standpoint, what we've seen, which has been a hot topic. Is it hard to zany datamab getting approved here? And we are seeing some exciting data in upper GI space as well with better side effect profile when compared to our historic chemo or ADCs. So Neil, again, thank you so much for walking us through your treatment approach. For BILIRI track cancers. For our listeners, let us go or a quick recap from today's discussion. In today's discussion with Dr. Neal Cmod, we had a chance to touch on the current treatment landscape for biliary tract cancer. For early disease, surgery remains the main stay with adjuvant chemotherapy. For that unresactable or locally advanced disease, chemo with radiation or leaning into our IR colleagues is important. But when it comes to metastatic disease, off front we tend to rely on Derva, Gensus, or Pembro Gensus, and they both resulted in similar outcomes, including overall survival roughly around 12 and a half months. Rollhead, then we touched on progressive disease. What are you walking away with? Right, Rahul. Before I move on to second line and beyond with biomarker, it is important to reiterate what was discussed that is one can skip the five FU bolus in advanced settings. And DpyD testing is now part of the label whenever utilizing five FU. With regards to second line and beyond biomarker testing is extremely important. We touched on her two positive space where we have options of Zanydatemab and TDXD, though very similar efficacy, but from side effect management standpoint, Zanydatemab is better tolerated, though it has side effects, especially diarrhea, but it can be controlled with the use of low paramide with regards to TDXD, which is rather an ADC. It has chemotherapy related side effects like alopecia, nausea, vomiting, fatigue, and not to forget the important one, ILD. Rahul, did I miss anything? We touched on her available options for IDH1 mutation and FGFR mutations. We clearly need more treatment options for this disease as overall outcomes are still poor. Thank you for tuning in. See you in our next episode. We are The Oncology Brothers.