Activity Transcript

Ghassan K. Abou-Alfa, MD, MBA: Hello. I'm Ghassan Abou-Alfa, a professor of medicine at the Memorial Sloan Kettering Cancer Center in New York. Welcome to this program titled, Targets to Treatments: Evaluating the Ongoing Evolution of the Care of Cholangiocarcinoma. Joining me today is Dr Nilofer Azad, who is professor of oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome.

Nilofer S. Azad, MD: Thank you.

Dr Abou-Alfa: Cholangiocarcinomas are particularly aggressive tumors, which are commonly diagnosed at a late stage, not amenable to surgery. And if anything, we have standard of care, including gemcitabine cisplatin, which offer survival of less than a year. However, cholangiocarcinoma can have distinct genomic signatures with oncogenic driver alterations that afford the opportunity for precision medicine. During today's program, we'll be looking at the clinical trial data for therapies in metastatic cholangiocarcinoma, molecular testing, and treatment considerations. And with this, I'll start by a case presentation, which Nilo and myself will try to kind of dissect and learn from each other, and of course, hopefully will relay some information to all of you.

If anything, this is 73-year-old Black man presents with a three-month history of weight loss, right upper quadrant abdominal pain, slowly increasing in intensity, but not limiting activity, and fatigue with eventual development of jaundice. Evaluation reviewed a large 8-cm hepatic mass with satellite lesions and periportal and intra-hepatic biliary dilatation. The CA 19-9 of course was elevated. It was 345. And the liver function tests showed some elevation, very subtle AST, 67; ALT, 45. Bilirubin was 5 though. ERCP did happen, and biopsy showed multiple differentiated adenocarcinoma.

A stent was placed thankfully, to relieve the jaundice, and bilirubin normalized within two weeks. And meanwhile, mutational genetic testing was done and ultimately it revealed an IDH1 mutation. In conversation with his oncologist, the patient stated that he's interested in therapy for his cancer, but does not feel that quality of life is just as important to him as longevity. He wants to live. Makes sense. What's reasonable for the first-line treatment of this patient, and what would the IDH1 direct would be appropriate? So Nilo, teach us about what's going on regard to that IDH1 in cholangiocarcinoma.

Dr Azad: Yeah, absolutely. So I think what we see here is of very classic case of how our cholangiocarcinoma patients often present. This is a patient that likely does not have resectable disease. That's the first thing that we're going to be looking at, but considering that they have a large mass with satellite lesions, resection right now really isn't standard-of-care appropriate. Bilirubin is elevated and so the intervention to make sure that we get that bilirubin down is important. And then mutations in intrahepatic cholangiocarcinoma, we see that in 20% to 25% of patients.

So more and more we're seeingmutations come out, and patients understandably have a question. Most people want to avoid chemotherapy if they can, so people understandably have the question: can I just move on to the targeted therapy that is now approved for my cancer, or do I really have to go through chemotherapy first? So I think it's very reasonable to look at the data to see why was ivosidenib approved in patients with cholangiocarcinoma that have mutations. And so this trial you're very familiar with, leading the trial was a randomized trial phase 3trial that was randomizing patients to ivosidenib versus placebo, but in the second line, or in pretreated cancer patients.

So, I think that's very important for us to recognize that we don't have data in the first line for this. And the trial was designed with a PFS endpoint and it met its PFS endpoint, but there was crossover. So you see here that PFS was significantly prolonged. Now this is not a magic bullet; as you can see, it was statistically significant, but we still have work to do for our mutation patients. And then when you look at the overall survival, there's definitely a trend towards improvement in overall survival, but very difficult to glean in the setting of a crossover study, right? And so it's not fair for us to say there's not an overall survival advantage in a crossover study, but we can say the way that this trial was designed, we don't see that OS benefit, and that's why just recently we've had approval of this drug.

The other thing, the patient mentions quality of life, and so the safety and adverse event parameters that we see in that trial are really important. I think what was shown in this trial very much mirrors my experience -- I'm sure many people's experience with this agent -- that you can have some GI toxicity, but it's generally mild toxicity and relatively easily managed, some fatigue, and really constitutional symptoms that are able to be well managed. So tolerability-wise, it's actually a nice agent, but just not in the first line.

So first-line therapy, still gemcitabine and cisplatin standard of care based on the ABC trial that was published over a decade ago, but this would be a very reasonable second choice option in second line, I mean.

Dr Abou-Alfa: Well, thanks so much Nilo. Wow, this is quite a bit, but let's try to dissect a little bit more through discussion of the following component. And number one, I would say let's start with the data because the data is the data. That's great to hear about this. You and I were heavily involved in regard to that effort. And yes, I like very much the way you said it. After all, we do acknowledge that we really required that we do a crossover study because we want to make sure to give an opportunity for all the patients on the study, not to feel that they were really not given the opportunity because they have the mutated .

And that's why the translation of the survival, as you said, it was more to use this kind of like statistical tool of the rank preserving that will interpret the survival data as if the patient remained on the placebo. And if anything, I would say yes, it was positive. We're very proud of it. We're very delighted that patients can access this drug. The question that I have for you, Nilo, is within that context and you already spoke about it. Patients come and say, "I have an mutation," and they didn't get any therapy yet. "Why don't give me the drug?" And you said... because as you said, it's not available first line. What will be arguments that you will use with the patients for that purpose to understand why we're holding it for second-line therapy?

Dr Azad: I very much understand both as a doctor taking care of patients and the patient themselves, the idea of a less toxic drug, a single agent that's oral being something that you would want to try before you try the standard of care chemotherapy option. I think the challenge is that we don't know whether we really need that initial benefit of chemotherapy to give people equivalent survival, right? So sequencing in terms of whether one treatment works as well if it's given first or second, that isn't established in this setting. So when I talk to patients, that's how I talk to them about it.

I acknowledge that this is difficult and I totally understand where they're coming from in terms of wanting to do the drug first, but that we don't know if long term we're not going to compromise their overall survival. My gut feeling is that in a well patient that we probably wouldn't, but that's just a gut feeling, so that's not the same as having real data. And I will tell you that when I treated patients with this drug, when it was first even in phase 1 studies, we had a handful of patients that really did well for six months, for a year. I had one a couple patients that were on for over a year and a half.

So, there is a tail on the ivosidenib curve where some people do well for a long time. It's 10% to 20%, but it's still meaningful. So I'm excited about this agent.

Dr Abou-Alfa: Yeah. I think you bring a very important point, which if anything, to translate what you very wisely said, the treatment plan for the patient with cholangiocarcinoma is not about what we're going to do right now. It's more about thinking not a only one step, thankfully not anymore to think about only one step, but about two steps, even three steps in regard to the therapy. And as such, it's not like if we say no to the ivosidenib in the start, it means that's it. Absolutely not. Actually, if anything, the data so far has been tested in the setting where obviously ivosidenib was used as second-line treatment.

Could it be in the future that we find out, for example, that the target therapy should come first? We don't know that yet. We just have to wait and see. But for now, the appropriate approach is to go, as we both agreed in the beginning, we go by the data, the data was done as second-line therapy, the chemotherapeutic intervention, yes, it has a lot of value. We should not please discredit, to all our colleagues listening to us, we should not discredit the value of chemotherapy. People can really do very well with chemotherapy as D. Azad said; patients can be on chemotherapy for a while before there's a certain progression or intolerance that will lead to the target therapy.

Good that we have that asset in hand to move on to the next line of treatment afterwards. With this said, I would like, and I have a last question for Dr Azad because wisely and I have to give credit, when I got that case from one of our colleagues and I thought, like that's it, this is great to kind of like interact and discuss with because a lot of learning points over here. But to give credit about when would we do the genetic testing? Your thoughts.

Dr Azad: I think that we should do genetic testing as soon as possible on these patients. And it's not just because of the story, but because as we're about to speak about the FGFR2 story is also very important. And we have multiple clinical trials right now that are enrolling patients in the first line. So we have more than one consideration, but right now there isn't a standard of care option in the first line that makes a difference in terms of standard of care, if you're being treated out in the community.

It sometimes takes a while to get the tissue though. And I'm not talking about how long it takes for the testing to get back, but too many times with our patients, the tissue is scanned and they have to have repeat biopsies performed. And so because of that, sending that as soon as possible, so that if we do need to repeat a biopsy, we have that opportunity before they need their targeted therapy option is really important. So it's the very first thing I do after that first visit with me.

Dr Abou-Alfa: No, that's very important. Please, this is a very important message from both of us. I mean, I jokingly say to the patient, like I say to my fellows, "If the patient's still on the street, that kind of cholangiocarcinoma, you better start doing the genetic testing, because yes, it takes a little bit of time. As you said, between obtaining tissue and to get the testing results. But as you see, the magic that happened to that patient, and that's why really, I was so happy about that case specifically to present, because when things did actually occur, the results of the genetic testing were already there. We were not waiting, creating frustration for the patient, loved ones, and ourselves. Everything was there. But it was a great segue.

And if anything, we'll move on to our next case as Dr Azad already suggested. And this time we have a 64-year-old lady with pathologic confirmed stage IV intrahepatic cholangiocarcinoma. Patient again was started on standard of care therapy with gemcitabine cisplatin. Exactly what we expected. Patient had a next-generation sequencing ordered from the start, exactly seems like they heard us. And if anything, the results were reported while still patients benefiting from the gemcitabine cisplatin. Good important thing did not stop the therapy, but at the same time, the next-generation sequencing demonstrated an FGFR2 fusion.

And the questions of course were brought in, in regard to gemcitabine cisplatin, patients kind of acceptingly doing okay with it, no issue of intolerance. At the same time, no progression yet. And the question for you, Nilo, now same scenario, but we're bringing a little bit of more variables. FGFR2 fusion. We know about it. We're excited about it. I know it's more uncommon, but patients still benefiting from gemcitabine cisplatin. Would you stop the GemCis, go to the FGFR2 fusion-targeted therapy, or what do you do?

Dr Azad: This is a little bit of, I think, individual doctors' philosophies. So my philosophy is that if a patient is on something and it's working for them, you don't switch them to something else unless they're not tolerating it. So if it's not broke, don't fix it. And that's because we don't know if we go back to GemCis later, whether the patient is going to have an equivalent response, or if we're going to upregulate resistance mechanisms, we just don't know.

So if a patient is tolerating GemCis well, I continue until they need to go on to the FGFR2 inhibitor either because they're not tolerating it, or a lot of times it's actually just needing a break for sanity. Patients need a break for many reasons beside it's just their platelet count is too low. And so that's my personal philosophy, but I really do think it's very reasonable for someone else to think that if you've got a targeted therapy that is as effective as an FGFR2 inhibitor, that you may want to consider doing that.

I think that I wouldn't fault someone significantly if they moved a patient off of it, if their patient was having any struggles early. But I don't think that there's the data to suggest that taking somebody off of a responding regimen and moving them to a drug that doesn't have 100% response rate is the right thing to do.

Dr Abou-Alfa: I totally concur with you. That's why we have to work together. We think the same way and you are absolutely right. If anything, if patients target it very well, let's not rush it. As we said, the process is not about what I'm doing right this second, but it's about really, how can I think in advance for other things that can occur. Because as you and I know, if we were to decide that the patient that said in regard to GemCis, that's it, they will never come back to it. And this is really what we have to be very careful about. Yes, if there's an intolerance issue and at the same time, if there's progression, I like the way you said it, we will not fault for the perception because of course, it can differ subjectively by the patient or their physician as well.

But let's say now we are at a position where we need to get to anti-FGFR2. So, wow. We never thought they'll have so many options available, but maybe we can go over some data. So maybe we'll start with the FIGHT-202 and the pemigatinib. Your thoughts on that, Nilo.

Dr Azad: Yeah. Absolutely. We now luckily have many tools in our war chest against FGFR2 fusions and FGFR2 rearrangements. And so the FIGHT-202 study is a study that resulted in our first indication for cholangiocarcinoma specifically, as you all know, FGFR2 inhibitors were approved in other indications, but in cholangiocarcinoma FIGHT-202 was a very important study. This was a trial where in the initial analysis, 107 patients were enrolled in the study and really saw about a third of those patients having very nice responses to therapy. So it was 35.5% to 37% in the repeat analysis where they added a patient.

And the other thing is that the durability of that response for a targeted agent was really, really acceptable. So the duration of response was 8 months. We know that targeted therapies aren't going to last forever as resistance mechanisms emerge, but having an over 6-month duration of response I think is quite compelling. And then the median overall survival was one and a half years for the patients with FGFR2 fusions and rearrangements.

And then of course, when we look at the toxicity that they were seeing, because we've got to always compare what our toxicity options are, because we now have other second- line chemotherapy options. Generally, I think again, a well-tolerated group of drugs, but they do have different toxicity than what we see with our standard chemotherapies, or even other targeted agents. So in particular, one of the on-target effects is a hyperphosphatemia that emerges in almost every patient that's treated with these. So the numbers put it at 50% to 70%. I really feel like it's something that we see very commonly in terms of having to manage, but it is manageable and you don't have to stop the agent because you have significant hyperphosphatemia.

I really want to emphasize that because I think it can be a little traumatic sometimes when you get that lab result back, but you do not have to stop it. And the other thing that's very common that's a little bit different is skin toxicities and hair toxicities. So our patients can get really long eyelashes that you think initially could be quite nice and then actually can get quite problematic. And then a lot of the same issues that can happen with constitutional symptoms and dysgeusia; some oral stomatitis can also be an issue. And that does often result in dose reduction from what I've seen.

Dr Abou-Alfa: Yeah, no, that's definitely quite important. And I'm so happy you brought up the adverse events that early. And as we both know, we kind of learned a lot from not only one drug. We spoke about pemigatinib with a quite impressive response rate, and this is already as we know available to our patients. But also we started before that with even another drug, which is infigratinib, which by all means had also great responses and had the same time, maybe the toxicities were a little bit relatively more apparent, because it was probably our first experience with it. But maybe you can share with us some kind of findings from the infigratinib data.

Dr Azad: Yeah. So the infigratinib trial initially came out first in terms of being first out in our cholangiocarcinoma patients. And I think we are seeing very similar toxicities in terms of the profile, but some of the actual individual toxicities, the prevalence looked a little bit different, but now that we have 4 different drugs that are now out and being tested. I think that what we can say is regardless of each individual agent, these are the toxicities that you can expect and you may need to adjust for as you treat your patient.

So whether or not you choose pemigatinib or infigratinib, we're going to soon have futibatinib, I think, that's going to be approved as well. And each of them, some of them have a little bit more hyperphosphatemia, a little bit less dermatitis, but broadly you're going to see very similar toxicities.

Dr Abou-Alfa: Yeah, by all means. Actually I personally would say, and I think you deferred to that as well, Nilo, that pemigatinib and infigratinib, almost kind of similar drugs because of the specific target for the FGFR2, even though, as we know the pemigatinib was looked also in other alterations, per se. Yes, we can talk or claim about the better response rate with regard to pemigatinib, but to be fair, this are all within the context of the phase 2 clinical trials that were done with them, which by the way, it's a novel approach that we can talk a little bit about in a second. But because you kind of quote on it already, and this is an important discussion as well, maybe we can at least talk about the other two drugs.

And let's start with the futibatinib because as you said, it is already kind of like moving along that path, same like pemigatinib and infigratinib. So what do you know about futibatinib?

Dr Azad: So futibatinib presently has enrolled a large phase 2 study and has been applied to the FDA for approval. And the thing that is nifty about this drug is that it allows potential response in patients who have had previous treatment with an FGFR inhibitor that may have developed a gatekeeper mutation as a resistance mutation. Now it doesn't target every resistance mutation, but the two most common resistance mutations, futibatinib can still be active in, and so I think it's a particularly exciting drug because it's like our second-generation agent.

And what I'm hoping is that we're going to be very much like our lung cancer colleagues, who once they identify a mutation or abnormality, they have first-generation, second-generation, even third-generation agents that can then still be active as they design drugs around the resistance mutations that occur.

Dr Abou-Alfa: No, that's very important. And I like that we brought up the futibatinib a little bit later in the game because no doubt that the targets, we have to remember FGFR is really a big name for many things that can occur among which diffusion as we know. And this was recently reported as well in regard to futibatinib value regard to being a target for FGFR1, 2, 3, and 4. And at the same time, we have other things that can occur besides fusion, which is mutation. And this would really bring in also derazantinib. And maybe we can talk few words about derazantinib as well.

Dr Azad: So derazantinib is also presently in the clinic and has already been reported out as well, showing a really beautiful waterfall plot in patients with FGFR2 fusions and rearrangements. There is also interest in trying find so many of our patients, as you mentioned, have FGFR2 fusion mutations, not just rearrangements. And so the question is whether we can find agents that might be able to be active even in that patient population. So that's the hope with some of the newer drugs though. We don't have strong data in that setting yet.

Dr Abou-Alfa: Yeah, no, if anything, this is great discussion in regard to FGFR2 and FGF alterations, if you want to call it that way. Number one, as Dr Azad mentioned to us, please, please, it's very important. If a patient is on and benefiting from, and tolerating their chemotherapy, it's not a bad thing. It's great. If anything, it's very important to really make the best out of the options that we have for patients, because after all we have to strategically think what's going to happen afterwards.

We're very excited that in the setting of the mutation we have ivosidenib, which now is probably FDA approved and accessible to all of us as second-line therapy. And with regard to the FGF, absolutely for the fusions, also we have the pemigatinib and Infigratinib approved. And to that, the good news is that now we are having even a better understanding about the toxicities and as more drugs are available to us. And by all means, I like how Dr Azad mentioned it.

After all. Yes, we're going to have hyperphosphatemia seen, but we should not have a knee jerk reaction, because ironically, I remember in infigratinib first study, we caused hypophosphatemia as a side effect because of our eagerness to solve hyperphosphatemia. So please kind of measure things from the clinical perspective, not only from the blood work. And I think we're having a better handle on how to manage those toxicities. And by all means, please, when we read next-generation sequencing report, not just say, or look at the colorful title FGF, we look at the details because as we just heard and we heard from Dr Azad again, for example, the futibatinib in regard to FGFR 1, 2, 3, 4, and potentially even overcoming a certain resistance beforehand, in regard to derazantinib, in regard to, again, the FGF mutation or fusions, add to even FGF mutations.

So by all means there's lot of options over here, but we have to of course, wait for more data or evolve with the data, so we can really continue to smartly choose the right therapy. With this kind of wrap-up of what we spoke about so far, no doubt that we touched on it in the beginning, but it's very important how to order the genetic testing. What should we do with that? What kind of need for specific testing? Is it the biopsy? Is it the cfDNA that we hear quite a bit about, or is it the need for repeat biopsies?

Please do remember that next-generation sequencing is more of a tool to kind of look at the pathology in more details. It's like it in a way, pathologists used to use a microscope, and now on top of that, they do next-generation sequencing. I personally would say that a report of pathology for a patient with cholangiocarcinoma, let's say, for example, adenocarcinoma consistent with biliary/cholangiocarcinoma which is classic many of us feel that way is technically incomplete until we have the next-generation sequencing results that will tell us about what the patients might have one way or the other.

Dr Azad: Absolutely.

Dr Abou-Alfa: Thank you. Thank you for agreeing to that. Absolutely. It's very important to relate to this because yes, we might claim that they are rare. Yes, it can be rare by the entity itself. For example, yes, they might not be that common even though in some claim up to 15%, 25%. In the FGFR2, probably a little bit less common. Maybe in the 5% to 15%. But ironically, if we add all those numbers together, I would say we can guesstimate that almost 50% of the patients with the intrahepatic cholangiocarcinoma might have a potential target for their therapy. So definitely it's very important component of taking care of the patient.

Dr Azad: Yeah. And I think one of the things that's interesting is that we don't think twice about sending testing on patients for MSI for colon cancer, which is only present in 3% to 5% of colorectal cancer. And everyone agrees at standard of care to do ALK and some of these mutations, and lung cancer can be present as low as 1% or 2% and every patient is sent for it. So I really think your point about the fact that among GI cancers, cholangiocarcinoma has the highest percentage of having something that's targetable. And so it is absolutely standard of care for these patients to be getting testing as part of their paradigm.

Dr Abou-Alfa: Absolutely. And along that line, for example, three other kind of alterations that we can target, maybe a little bit relatively less common specifically for intrahepatic cholangiocarcinoma can occur if anything, for the BRAFV600E yes, can occur. Maybe not that common, but if anything, there has been already a study that looked at dabrafenib plus trametinib and showed that there's clearly an improvement or response that kind of will translate into, yes, this combination for patient with BRAFV600E biliary cancers among which intrahepatic cholangiocarcinoma would be a choice.

Same thing for the HER2. As we know, HER2 yes. Maybe it is more gall bladder cancer, but has it been reported in intrahepatic cholangiocarcinoma by all means that has been. And for example, there has been many studies among which one that we're very proud of. Both of us that were part of the MyPathway looked into pertuzumab plus trastuzumab for HER2-positive biliary cancers. It showed again great responses. You notice the subject of responses coming back and forth because this really is what mainly we focus on understandably in regard to the phase 2 trial.

And of course, we have also the MSI-high, which yes, it's not that common, but yes, it can happen. Less than 5% of the patients, but yes, it can happen. Or, of course the anti-PD1 like pembrolizumab will apply as well. So please, again, genetic testing is very critical. Do it as early as we can, as Dr Azad mentioned. At same time, use this as money in the bank, because down the road, you might need those potential options for the patients to address whatever therapy per se. Now, with this said, however, back to Dr Azad.

Dr Abou-Alfa: And, Nilo, interestingly, the question that we brought up in the beginning about, after all, at the moment, the data is mainly in the second line. That's why we have to do still our chemotherapy intervention. But as you, and I know, and we're part of, there are many trials that are looking into for example, the different anti-FGFR2 versus standard chemotherapy in first-line setting. Your thoughts about those studies.

Dr Azad: So I think those studies are very important. So pemigatinib, infigratinib, and futibatinib are all being tested in the first line. The trial designs are very similar. Single-agent FGFR inhibitor versus gemcitabine cisplatin in the first line. So they're very important to answer this question, especially when we have agents like FGFR2 inhibitors that have such high response rates and nice durability of response.

The challenge with these trials is A, they're redundant to each other. And B, this is a small percentage of patients, so 15% of intrahepatic cholangiocarcinoma. So the studies are really struggling to enroll, because over the last couple of years, as these trials have moved forward, they've really only been able to enroll handfuls of patients on each of the studies.

There are some ways that they may be trying to correct that, but for this group in this audience, if you do end up having a patient that has an FGFR2 fusion, and you haven't started them on therapy, please do reach out to a major academic center around you if you don't have a one of these trials open, because there's probably one close to you that has these trials, and we really are going to need the help of the entire cancer community to be able to enroll these trials.

Dr Abou-Alfa: Well, thanks so much, Nilo. If anything, you bring in and we'll probably philosophize a little bit here, but that's totally fair, because this is really an important struggle. These are relatively uncommon genetic alterations, relatively speaking. We're excited, we have plenty of phase two data that we just spoke about, and we're delighted to see that yes, many of those drugs already have been approved. Like ivosidenib, pemigatinib, and infigratinib.

On the other hand, now we're trying to really kind of assess their value and assess in the first-line setting. And as you said, big clinical trials, very well-intended, were all responsible for and were part of many of them. But at the same time, accrual has been limited. Ironically, based on clinical trials, if you take any of those studies and you try to calculate what's going to finish, you and I will be on the beach by then. It's 42 years. And the question is, what are we doing here? And my question to you is the following: back in the '60s and '70s, understandably, we compared whatever chemotherapy, whatever combination of chemotherapy to a best supportive care, to a placebo, or even when we added therapy to the standard of care, in other words, we compared two drugs compared to the one that was by itself, standard of care.

Now, the question is, that language was great and continues to be great in the setting, especially of what's called stoichiometric therapy, where more is probably more effective, but of course more can cause more toxicity. But now we're totally different world. Number one, it's a very, very boutique-like where specific mutations, specific genetic alteration in a rare disease to begin with. And the question is, could it be that all in all, and I'm not trying to kind of point any fingers over here, but could we all in all, probably not doing it right? In other words, we're not asking the right questions?

Dr Azad: I think that that is a major problem in terms of how do you marry a perfect biological test or clinical trial test with the reality and feasibility of what we actually see on a day to day basis? Because that is the question. The question should be, how can we help patients on a day to day basis? Not, can we answer in some very pure sense whether chemotherapy versus this agent is better? And I think that that is the challenge that we got into, and it all came from good intentions. But the real question should be in my opinion, how can we most quickly get good drugs into patients as soon as possible, and then design a trial around that mission? Because otherwise, we're going to end up 42 years later, wondering about this.

Yeah, I totally agree with you. And I would just wonder, because no doubt that, and I kind of preluded that was going to be more a philosophical discussion here, but survival is key and no doubt, however, I really am delighted to see that we are dependent more on certain what we consider to be alternative approaches, but at the same time, reflecting survival ultimately being progression-free survival or even response rate per se. And I wonder if really maybe after all, in settings of specific genetic alterations, and at the same time, rare diseases. Why not just kind of accept the data as is?

Dr Abou-Alfa: Because I would say a trial that, for example, putting patients with these certain genetic alteration-targeted therapy followed by chemo, versus chemo followed, but we might probably learn more from then kind of trying to see still in genetic alteration what might happen. But anyway, here, you and I can talk as much as we like, but hopefully our colleagues will kind of engage in the discussion, because to be fair a gift card for everybody, everyone's struggling with the same question.

I think that was a great, great discussion. If anything, we learned quite a bit in regard to the different genetic alteration therapies. And if anything, we again touched on the mutated with ivosidenib. We also touched on the FGFR2 different alterations. We spoke about pemigatinib and infigratinib, which are readily available already for us as well. And also, we brought in the need. And please again, this is probably... if you were to remember anything from what we spoke about, I totally agree with Dr Azad, please, genetic sequencing as early as possible. Don't deny the patients the opportunities that they can get from different therapies.

Of course, as we said, we're still struggling with certain sequencing issues that hopefully future studies and future perspectives will probably help translate that into something that's more active for patients. If anything, Nilo, I can't thank enough for a great discussion.

Dr Azad: Thank you so much, Ghassan. It was wonderful.

Dr Abou-Alfa: And thank you for participating in this activity. Please continue on to answer the questions and follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.