Treatment of Hepatocellular Carcinoma (HCC)

Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet the Professor, as today we talk about the management of hepatobiliary cancers with Dr Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center in New York City. We’re going to do 2 programs, another one with Dr Kelley. And if you have any questions or cases you’d like to run through — run by Dr Abou-Alfa, just type them into the chat room and we'll talk about as many of those as we have time.

If you’re into audio programs, we have a new program coming out on biliary tract cancers with Dr Valle. And we know a lot of people end up listening to these webinars. So check out our Oncology Today podcast series.

We do webinars all the time. Next week, we’ll be doing one on upper GI cancers with Dr Klempner from MGH. The next day, we’ll be working with Dr Stone from Dana-Farber, talking about AML and MDS and the recent ASCO and EHA data. And then, we’ll continue our CML series with Dr DeAngelo on July 19^th. And then we’ll finish up this series on July 28^th with Dr Kelley. We have our ovarian cancer program. We’ll have another program there on August 3^rd with Dr Ledermann. And then on Saturday, August 6^th, I’m actually getting on an airplane, folks, and heading out to the Bellagio in Las Vegas to work with the American Oncology Network. We’ll be there all day on Saturday, the 6^th, but we’re also simulcasting it. We’ll be covering about 15 different tumor types. You can see we have about 12 investigators. They’re all going to be virtual, but I’ll be with the AON people in Vegas. If you want to hop on a plane and join us there, we’d love to see you.  

But today, we're going to talk about hepatobiliary cancers. And a lot to talk about, particularly since the GI Symposium earlier this year in January in San Francisco. Two big trials, first line therapy, that we’re going to get into. As always, we’ve got a bunch of cases from the real world from general medical oncologists that we’ll present here today to get some feedback on, make some rounds.

I just want to start out reminding you, Ghassan, about the satellite we did in the GI Symposium. Actually, it was just a couple hours after you had presented the HIMALAYA study. Tony Saab was the moderator. I was sitting back in Miami kind of watching the whole thing, communicating with Tony by Instant Message. We’ll talk a little bit about some of the things that were discussed then and get an update from you about your thinking and what you’re hearing from your other colleagues in the last 6 months about these 2 really important first line trials.

We’re splitting up the program here. We’re going to start out talking about HCC. Then, we’ll talk about biliary tract cancers. And then, as always, we have an appendix with a lot of great trials and data for you to sift through and check out.

Case: A woman in her early 50s with metastatic hepatoid carcinoma of the ovary with an FGFR fusion — Syed M Ahmed, MD, PhD

DR LOVE: But I want to just start out, first of all, I want to ask you about this case that we presented to Dr Shannon Westin in our ovarian cancer series a couple weeks, a few weeks ago. This is a patient of Dr Ahmed from Illinois, a young patient who has extensive metastatic disease and is thought to have “a hepatoid cancer of the ovary”. Also, has an FGFR fusion. Dr Westin had never heard about it and never seen a case of it. We asked Dr Matulonis, another Gyn oncologist, last night. She never saw a case of it. I was telling you about it. This patient had alpha-fetoprotein of 14,000. Ran out of options. I was thinking well maybe you ought to try a checkpoint inhibitor, something like HCC. And then, I was asking you about it and, of course, you said you published on it. But anyhow. What’s the deal with hepatoid cancer of the ovary or hepatoid cancers? And is something like atezo/bev or, this patient never had an IO, should you consider it in a situation like this, Ghassan?

DR ABOU-ALFA: Thanks so much, Neil. If anything, to really reassure Dr Ahmed, it’s not so oft that I’m going to say, oh yeah, of course, I know it and it’s a very familiar thing. Because to be fair, it’s uncommon. But nonetheless, because of the referral nature of what we do at Sloan Kettering, we do see hepatoid. If anything, I mentioned to you that we have seen hepatoid in the pancreas, i.e., it’s liver cancer with no primary in the liver, but simply showing up in the pancreas. And we also have seen gastroesophageal hepatoid which really had features kind of like a mixed bag between the gastric cancer and hepatocellular carcinoma, again, without any presence at all in the liver. We don’t know really how these etiologies evolve. But what we know is that the treatment has to be really kind of dissected based on the best 3 that we have in regard to where the pathology is coming from, even though we know very well there’s quite a bit of conversions throughout the therapy among which, of course, the use of checkpoint inhibitors in regard to some of the diseases.

DR LOVE: So this patient also, as you can see, has an FGFR fusion. So I don’t know if there’s sort of a mixed element, maybe he has biliary tract. Would you consider an FGR inhibitor in a patient like that?

DR ABOU-ALFA: Absolutely. Actually, and to bring your point in point here, FGFR2 fusions are not, sadly, only in cholangiocarcinoma. They have been noted rarely, but you can see in HCC.

DR LOVE: Really?

DR ABOU-ALFA: And number 2 is interestingly, alpha-fetoprotein level is actually a potential marker for gastric cancer to begin with. So it’s not, sadly, only the HCCs that does that. And if anything, a classic, which I’m sure some of your colleagues know, I can associate biliary cancer with high AFP as gastric cancer until proven otherwise.

DR LOVE: I was joking with Ghassan before the meeting that I feel like all day long, I’m making this statement. Wow, we do a million programs on this topic and I never heard that before. I feel like I’m saying that all day long. I hear new things every day. It’s unbelievable how much stuff is out there. Anyhow.

Key recent data sets

DR LOVE: Let’s dig into HIMALAYA because when I was sitting back here in Miami, as we got to the end of the meeting, I sent Tony a text. I said, Tony, why don’t you ask everybody what they think the ideal first line therapy is? And, of course, everybody else on the panel said, in general, atezo/bev unless I can’t give them bev and then, okay, I would use HIMALAYA. But you just came right out and said I think this ought to be first line therapy. That led to pretty interesting discussion. So I want to get a follow-up on where you are today. Here’s your presentation from the meeting. And, of course, it went right into the New England Journal, the New England Journal Evidence, now the second New England Journal paper. And, of course, the key thing there was the survival. Maybe you could just sort of comment on, from your point of view, first of all, maybe a little bit about the design and why you chose the, particularly, the way you give the anti-CTLA-4, the tremelimumab, the background, the design of the study and the key findings.

DR ABOU-ALFA: Absolutely. So if anything, number 1, the idea about dual checkpoint inhibitors is relatively novel. And the idea will depend on that at the cell membrane level of the cancer cells, the anti-PD-1 or anti-PD-L1 activity will literally permit or facilitate the immune cells to attack the cancer. But it seems none of this happens without a phone call from the higher chain of command. And this is where CTLA-4 sits in the lymph node kind of inside that activity, per se. What’s fascinating is that it seems one phone call is good enough. And not only that, but this phone call for anti-CTLA-4 activity, fascinating, is more potent than CD28 which is the normal way the activity does occur. So no doubt that it’s like what I kind of called a jumpstart like same like we do with our batteries for the car. And simply, once you jumpstart it once, you then push on the gas which is durvalumab that can carry on with you.

DR LOVE: So before you get into the actual results, just to take a step back, because one obvious thing that is very different about this compared to the other combination everybody knows about, ipi/nivo, that is approved is the way it’s given. You only give the tremelimumab once and then that’s it based on the kind of thinking you have. But, of course, ipi/nivo has kind of a reputation and a lot of data for having a lot of autoimmune toxicity. What about with this kind of schedule and a different drug? Same thing or less?

DR ABOU-ALFA: So quite fascinating. So before the HIMALAYA study, there was a Phase II clinical trial which already is published in JCO. And in it, actually, we found that actually 4 doses across every 4 weeks of the tremelimumab at a lower dose of 75 mg compared to the one dose of 300 in the HIMALAYA, interestingly, those 4 doses of tremelimumab plus durvalumab did not fare any better than durvalumab as single agent. So in other words, it did not really kind of help that activity of the enhancement of the anti-PD-L1 activity of durvalumab. So as such, the HIMALAYA originally had 4 arms. One of them was actually 75 mg of tremelimumab times 4 and it was actually taken away and we kept only the 300 mg one single dose, per se. Which is quite fascinating if you think about it. What’s in oncology that gives one drug in one patient’s lifetime only once? Amazing.

DR LOVE: But, again, getting back to toxicity with all the problems or challenges of comparing indirectly, even I’m curious about your own personal experience. Again, ipi/nivo, you know autoimmune hepatitis, colitis, et cetera. Do you see the same thing here?

DR ABOU-ALFA: So jokingly, I’ll tell you that historically, the first study that we did on ipi was colorectal cancer. Every patient was admitted to the hospital. We did it here. And now, we know very well that the colitis and the gastric — the colorectal events can really be a problem. Interestingly, with the tremelimumab/durvalumab, we did not see that much of in the HIMALAYA study. And no doubt that, in other words, other than the potency that I tried to stress out first, yes, you’re right. Also, it’s about the tolerability and the reduced adverse events. But I want to make sure to illustrate first the efficacy before we come to, yes, it’s definitely better tolerated with one dose only of tremelimumab.

DR LOVE: Absolutely. And, of course, here’s the key finding in terms of overall survival. Do you want to comment on that?

DR ABOU-ALFA: Sure, by all means. So this is, you know, all of us are, in our mind, trained to look at the median. And, yes, the median is definitely showing an improvement in survival. And if you recall, as we can see it over here, the STRIDE, which by the way, STRIDE stands for the exact regimen of one dose of tremelimumab at 300 mg plus durvalumab, 16.4 months. Sorafenib is 13.77 months. This was clinically and statistically significant. The second endpoint of the study was to look into the — and we’ll go back to the previous slide. The second point of the study was to look into the noninferiority of durvalumab as anti-PD-L1 versus sorafenib. And this is, of course, based on the data already there in regard to nivo, pembro and other checkpoint inhibitors where there’s no difference to regard to TKI. And, again, 16.56 months versus 13.77. But please, please, I urge everybody not to compare those numbers. In other words, 16.43 of the STRIDE is based on superiority compared to the sorafenib while the 16.56 of the durvalumab is based on noninferiority. So those two 16’s are not the same, i.e., it’s not enough to say oh, I could just do durvalumab without the treme. No, the treme is very much needed to get the benefit that we’re talking about.

DR LOVE: So what about PFS?

DR ABOU-ALFA: Sure. So to carry on, one more comment in regard to the survival. We spoke about median and we commented on median but interestingly, we know very well in immunotherapy, the cells are being primed. It’s kind of like, how to say, you just call them, you recruit them and they want to be trained to how to attack the cancer. As such, that’s why we kind of use this misnomer or, you know, we use it, the right and left, long tails of the curve simply because until these cells get ready, it takes a while. So that’s why median might not necessarily be the right place. And interestingly, as we have seen with survival, at 36 months, i.e., 3 years, one-third of the patients with the T300+D or the STRIDE were still alive.

Now when it comes to the PFS, probably my first answer would be in regard to checkpoint inhibitors specifically, who cares? Because we have seen that to be fair in both the IMbrave150 where the difference was super subtle between the atezolizumab, bevacizumab and the sorafenib, I think 6 versus 4 months or so. And over here, we barely see any kind of like connection at all between the 2 things. Because, again, one more time, these kind of events take a while until they cause their effect. Maybe early priming can occur with some T-cells that already are there. Like, for example, we have seen that the time to response was only 2 months with the T300+D but, however, the priming takes a while until you make sure those and be ready to get the response, per se, which the PFS will not be able to catch for you.

DR LOVE: So here’s another important issue, response rate. That was one of the things that stood out with atezo/bev, that you had a higher response rate. You actually saw responses which you really don’t see very much with sorafenib. Again, kind of — any comments about response rate? Seems indirectly similar. There was an improved response rate, similar to atezo/bev.

DR ABOU-ALFA: Yeah, but only as #1. You’re absolutely right, Neil, that the TKIs exemplified by the first one that was studied, we started the first Phase I on this — Phase II on this at Sloan Kettering, definitely did not show any response. However, interestingly, with the checkpoint inhibitors, yes, responses do happen. To be fair, we have seen even CRs. We have seen, as you can see over here, about 3% or so. The IMbrave150, there were 7%. People come to me and say, but there’s more complete response in the IMbrave150 compared to survival. Again, these are not to be compared. And we’re going to comment a little bit to other perspectives that are important in regard to who are the patients on those 2 studies. But nonetheless, at least we can say for the 2 studies, yes, responses are seen. By all means, it’s definitely possible because of the use of the checkpoint inhibitors.

DR LOVE: So I want to kind of move into kind of clinical implications. I encourage the audience to check out the slides that we put in the slide deck. We have the update from the IMbrave study. And then we also put in there this paper from the COSMIC trial looking at cabo/atezo. So you can check those out. But we put it all together with a couple of comparisons. So, Ghassan, here’s, we have IMbrave and ORIENT, both looking at IO plus bev. Two completely different studies that had almost identical results. And you look over at COSMIC where there was a lot of excitement about TKI plus IO. But there, you don’t see a survival benefit. Any thoughts about the future of that kind of strategy with HCC? Lenvatinib/pembro, for example.

DR ABOU-ALFA: No doubt that the way we have to think about the anti-PD-1, anti-PD-L1 is like the scaffolding of a building. And now, it’s a matter of what do you throw in in regard to the walls on that building. It could be anti-VEGF like, for example, bevacizumab. It could be a c-MET inhibitor like, for example, cabozantinib, et cetera, et cetera. Interestingly, it appears to be this scaffold did not really fare better or didn’t get strengthened by the use of c-MET inhibition. And I think biologically, there’s a limitation in regard to what cabozantinib could have done in that matter because, as we know, the overall survival did not really matter at all. And there was a little bit of a technical probably challenge in regard to that study, the COSMIC-312, where they put the primary endpoint as PFS. And we just said, PFS in regard to difference is not really what you should look at first. It should be the OS. So I think there was kind of probably a revisitation of that. But #2, I think even if we were to redo it, it’s still the survival did not fare well because truly maybe because of the almost remote activity that the c-MET inhibition, AXL, VEGF of the cabozantinib occur does not crisscross with so many of those connectivities between the lymph node and the similar brain level.

DR LOVE: So we always say before we put these slides up, all the caveats of indirect comparisons. We all know that. But on the other hand, that’s all we have sometimes. And, of course, here’s the one of great interest comparing atezo/bev to the STRIDE regimen. Any thoughts? Grossly, the numbers look pretty similar. Any thoughts?

DR ABOU-ALFA: Sure. I totally agree that it’s very important not to really compare. And for that reason, we have to remember, we cannot say 19 is longer — is a bigger number than 16. Remember, it depends which currency you’re using. Is it all in dollars or is it euro and dollars? Who knows? Because interestingly, if we look at the demographics of those 2 studies, in the IMbrave150, 50+% of the patients were hepatitis B while in the HIMALAYA, only 30% were hepatitis B. HIMALAYA actually had a little bit of a global presence of 30% hep B, 30% hep C and about 50 — correction, 40% with the nonalcoholic fatty liver disease plus nonviral. While in the IMbrave, it was literally 50+% hep B, 20% of hep C and about 30% of the nonalcoholic fatty liver. And this really already brings into us that these numbers are not to be compared. Theoretically, if we were to repeat those studies with the same demographics for either or, I’m sure we’re going to get different results from what you are seeing over here. So please, it has to be understood. I like the way you said it, Neil, they pretty much both are good therapies. That’s really probably the best answer we have.

DR LOVE: And, of course, we know that you have to make a choice. And a lot of times, there are a couple of choices that are very similar. Sometimes, they’re almost identical. Extensive stage small cell, literally, those 2 trials look exactly identical. Here, obviously, a little bit different in terms of in comparison. But bottom line, you have to take the clinical data, take your clinical experience. You’ve got a patient sitting in front of them. And I guess my question to you is, in general, right now, putting aside reimbursement, assuming you could access either STRIDE or IMbrave, do you have a preference? And if so, why?

DR ABOU-ALFA: Absolutely. I would definitely go for the durva/treme. And the reason is the following. Number 1, it’s a good study. And I’m not saying that the other one is not. But we have to remember, it’s way easier to maneuver and to give the durva/treme because, #1, I don’t need to scope people which, if anything, scoping is not an easy business. It’s not like I put the scope in and I’m going to get a sign green or red or on/off switch or yes/no. It’s going to be like an endless interpretation which, if anything, number 1, I want to make sure we do the scope, but more importantly, we don’t want to under-evaluate the scope, i.e., by saying not to worry about. Or over-evaluate it where we say this is really a varix, we should avoid the therapy.

The other component that I’m a little bit nervous about which, interestingly, the FDA was the first to report it to us, is the issue of the antidrug antibody, i.e., allergy to the drug that we don’t know about. It’s almost like giving peanuts for a kindergarten child. If anything, the chance for an antidrug antibody for the durvalumab, for the pembrolizumab is only about 1.5%. For the atezolizumab, it’s 30 — it’s 50%. And in the IMbrave150, they did that study, give them credit, and they published it at AACR last year. It is 30%. At least — we don’t know how to test it, we can’t test for it, but at least, the obligation that we have is to tell patients about the antidrug antibody because if the antidrug antibody is positive, the atezo/bev, this whole thing, is as good as sorafenib, nothing more than that.

DR LOVE: So we have such a great chat room. I’ll put our chat room against anybody’s chat room. They already brought up the, I didn’t even know about the autoantibodies, Hassan in the chat room is already asking about it. Incidentally, he also asked the question, do you approach patients differently based on the etiology? Like hep C, hep B, NASH. Does that change, in any way, your thoughts about first line therapy?

DR ABOU-ALFA: Historically, we always focused only on etiology. And if you remember, even when we did the work on the sorafenib, we really dissected that maybe hep C patients might fare better with the sorafenib. However, we ultimately ended up saying that sorafenib is good for everybody. Maybe, yes, some people fare a little bit more or better than others but ultimately, it’s good for everybody. Interestingly, in regard to the combination therapy that we have currently, yes, people can differ in regard to the magnitude of benefit, but everybody will still benefit. That’s why I mentioned that 50%+ of the IMbrave150 is actually patients with hepatitis B which really fare better outcome. We know hep B patients do fare better. Interestingly, in the HIMALAYA, the patients with hep B, the hazard ratio was about 0.66. But it was a little bit higher in regard to patients with the hepatitis C and the NASH. Still, I would use it for everybody independent. And at the moment, I would not focus on that by saying as we heard beforehand from Pfister’s data that nonvirals don’t fare that well on checkpoint inhibitors. They still fare good, maybe not to the same magnitude, but they still benefit from it. Ultimately, the future is further dissection of the disease. We have not had it yet. But it’s some of the work that we’re doing at Sloan Kettering which is the tumor immune microenvironment, understand better many variables, not only simply etiology, but that can really tell you not only who will benefit, but more importantly, which therapy patients will benefit from. And this will probably turn the field of oncology from a guess work, let’s see if you benefit on the therapy, to a determined knowing that if patients get this, they’re going to benefit from it.

Case: A man in his mid 60s with a history of Child-Pugh B cirrhosis and Grade 1 esophageal varices who is receiving atezolizumab/bevacizumab for multifocal HCC — Raji Shameem, MD

DR LOVE: So I’m sure you have the audience’s complete attention at this point in terms of the perspective that you just described. I’m going to give you a chance to defend it looking at real-world cases. So we have 4 cases of HCC. I’m just going to get your brief take on the issues and the questions that these docs had, but also giving some thought to some of the comments you’ve just been making about how you think through first line therapy. We can see how that might apply to some of these cases, including particularly this one. I want you to think about if this patient had gotten the STRIDE approach, would you think anything would be any different? This is a 66-year-old man of Dr Shameem from Deland, Florida. Here’s the case.

DR SHAMEEM: 66-year-old male, multiple comorbidities, COPD, alcohol-/tobacco-dependence. He presented in April of this year due to abdominal pain. Got so bad he had to go to the ER. They did a CAT scan of the belly; showed cirrhosis, which apparently was a new diagnosis for him. A really large right hepatic lobe mass that measured up to 16 cm. Mass effect on the IVC. An additional segment 2 mass as well. Suspicious periportal adenopathy. AFP markedly elevated at 900. Hepatitis serology was negative. Child-Pugh Class B. Some episodes of melena. Endoscopy showed Grade 1 varices. So he had a beta-blocker that was initiated.

DR LOVE: How did he do on the atezo/bev?

DR SHAMEEM: He tolerated treatment pretty well. No immunotherapy-related toxicity. Stable disease. Sometimes when you refer them for local therapy, there’s delays. It can take some time to get it set up and the patients can really deteriorate really quickly. I just wanted to ask how the experts, felt about how they use local therapies in patients who are started on atezolizumab and bevacizumab? And the second question I have, second-line therapy? We have multiple agents available now. I just wanted to see how the experts would pick their second-line option?

Child Class B, I have treated because there’s not a lot of other options available. I’d also be interested in what their experience has been.

DR LOVE: Any thoughts?

DR ABOU-ALFA: 4 points that actually bring us over here. Point #1, in regard to the cirrhosis. I’m a little bit nerved up about what was done despite Child-Pugh B. I’m glad the patient did well, and I’m not surprised. Just remember, it’s an n of 1. Of course, patients can do well. But Child-Pugh B is a very, very broad spectrum. Is it the B7 that could easily become magically an A6? Or is the B8, B9? My guess is probably it’s in the B7 range. And if anything, please, please, it’s very important to be careful because, as we know, the Child-Pugh is not the flavor, it’s really a curve. And the curve is not a linear curve. It is actually an exponential curve. And it is a long, long line. That’s why I’m not surprised that the patient didn’t even know there was cirrhosis because there’s a long line. B is a curve and C is a shoot. And interestingly, if we catch people with Child-Pugh B at the start of the curve, yes, they can do okay. But at the end of the curve, they can shoot into Child-Pugh C and there could be detrimental effects. So please, please, you have to be careful with that.

Number two is, what is the standard for a patient with severely robust Child-Pugh B? Sadly, we don’t have a choice. It does not mean that we should be frustrated ourselves. The right choice is actually best supportive care because people will die from the liver disease before the cancer. The liver cancer becomes sitting in the back and, if anything, the person who is driving the car is actually the liver cirrhosis itself.

Point number 2, in regard to the point about local therapy, systemic therapy. I kind of would say that you did the right thing, I’m thinking, at least, in regard to systemic therapy because already our colleague, Dr Kudo from Japan, spoke to us about something called the up to 7 criteria where you count how many lesions you have in the liver. Let’s say, as an example, you have 4, so 4 as the number. You add the size of the largest lesion in the liver. Let’s say 4 cm. 4+4=8. It’s more than 7. Interestingly, he did this study comparing systemic therapy to local therapy in patients with more than up to 7 criteria. And guess what? The patients with the systemic therapy did fare better than they did with the local therapy. And I would say, I’m not trying to say, okay, now we’re going to grab those patients as get them as medical oncologists. No. If anything, it’s an invitation to make sure that we have always tumor boards, multidisciplinary team discussion and make sure that we go back and forth through that discussion to be able to get those points, per se.

Third point in regard to your therapeutic interventions. I’m a little bit nerved up with the varices despite they are really subtle, but take my word, when a varix opens up, and I’m sure many of us during our medical training we have seen them will develop kind of, you know, a balloon in the emergency room, it does not stop. This is extremely high pressure that can lead to death. And we have seen that with the bevacizumab single agent therapy for HCC. So I would say the best criteria we can say, if a varix did occur, was appropriate therapy stability for 6 months without any intervention at all? Yes, maybe I can revisit the idea of bevacizumab. But if it’s not really that, we should be very careful because really people can have serious consequence from that therapy.

DR LOVE: Any comments on his question about, of course, everybody has this question, about second line therapy?

DR ABOU-ALFA: Sure. I wanted to take a breath. But by all means, second line therapy is a very important point. Number 1, I recall I spoke about that, I introduced it right before the pandemic. And this was at the TAG meeting in Salt Lake — in Park City, Utah. And I taught about what’s called line minus 1, ie, if we give somebody atezo/bev, if we give somebody durva/treme, are we going throw away the option of lenvatinib and sorafenib as first line? Probably not because after all, they are very valuable assets for patients. That’s why I said maybe we’ll move on to line minus 1 so we don’t really kill the first line therapy. And as such, in regard to first line treatment, if it was atezo/bev as you just mentioned, second line therapy could simply be a TKI like lenvatinib and third line would be cabozantinib as an example as well.

Interestingly, however, one thing that will not be surprising, we’re going to see more and more of is that what if we try to challenge the patient again with checkpoint inhibitor? This is coming. And we already did some part of that in the HIMALAYA. Nobody asked me yet, but what happened, we had 70 patients out of the 1,400 on the HIMALAYA that actually we threw in a challenging dose of the tremelimumab afterwards when things were not really as great to try to rechallenge them and see what happens. To be fair, we don’t have that data analyzed yet because anyway it's a very small, teeny-weeny sample. But I would not be surprised that kind of your strengthening of that scaffold that we were talking about of checkpoint inhibitors is going to come one day. We’re not there yet, but at the moment, the sequence should not at least denude the option of the first line therapy like the sorafenib and lenvatinib as we just said.

Case: A man in his late 60s with previously treated HCC cirrhosis who is now diagnosed with potentially resectable HCC — Syed F Zafar, MD

DR LOVE: So I’ve got about 1,000 questions, but I want to try to get through some more cases. So let’s go to this next one. We’ll try to pick up some more questions after that. 69-year-old man who is a patient of Dr Zafar. This patient actually initially was thought maybe even to be potentially resectable, but the patient didn’t want to go that route. Here’s the case.

DR ZAFAR: 69-year-old, HCV cirrhosis, had direct antiviral treatment some time ago, cleared up his hepatitis C. Surveillance revealed 3 lesions that would not preclude transplant. He was BCLC Stage A low-compensated cirrhosis. So he refused transplant. We have this argument all the time, and everybody will toot their own horn. The IR guys will say all right, they can control it, and then the hepatobiliary surgeons, they’re not too sure about what route to take. And we feel that some of these patients could benefit from early systemic treatment.

But I would be interested to know if the faculty has some insight into it to when they would move on with systemic treatment in multifocal disease after locoregional treatment if there’s still room for locoregional treatment, but there is a concern about further synthetic dysfunction of the liver.

DR LOVE: Any thoughts?

DR ABOU-ALFA: Sure. So that’s interestingly a situation that we all face, and nobody could dare to give an answer to except our colleagues in Japan. If anything, they defined very clearly 3 embolization with no less than 3 months in between. This was because of the failure of the local therapy and you have to move on to systemic therapy. At the same time, we spoke about the up to 7 criteria a second ago, and also can be used, per se. But, again, one more time, we don’t want really to kind of like put rules and regimented kind of processes, but I will say it’s very important to make sure that we are present at the tumor board. I have to be a little bit harsh on our colleagues in oncology. Sadly, I have noticed through my kind of like ample interaction with everybody around the world, the group that is the least to be present at the tumor board for liver cancer is the oncologist. Please be there. Because believe it or not, our colleagues have no clue even what we have in regard to novel therapies. And if we’re not on the table, guess what, they might offer hospice care.

DR LOVE: Absolutely. They show up in your office with a liver that’s in bad condition and you can’t even give systemic therapy. Getting back to the chat room, Richard brings up a traditional question, but I’ll throw it out there again. How often do you have to biopsy to confirm the diagnosis of HCC?

DR ABOU-ALFA: Often, every time. We should definitely biopsy. Let’s explain this. This is a very important point. Thanks so much for the question. #1, if a tumor is resectable, like everything we do in oncology, I can understand totally you will go and take it out. If it is local therapy, of course, it’s local intervention per se, we can also accept to do local intervention without biopsy. When it comes to systemic therapy, a biopsy is very much needed because you want to confirm the diagnosis, you want to make sure that also we will not, for example, as we mentioned a second ago, have, for example, combined cholangiocarcinoma-HCC. Interestingly, I might get a counterargument that probably is being thrown in the chat as we speak in regard to what about LI-RAD 5? Interestingly, the LI-RAD criteria, and I spoke with the colleagues who did the LI-RAD themselves, it’s a language or a dictionary for the radiologists to talk to each other. Interestingly, if you have a LI-RAD 5 lesion which is 1 cm, you probably are very close to 100% this is HCC with one caveat, it’s with cirrhosis. The question is how do you define cirrhosis? I’ll tell you. Whoever defines cirrhosis correctly will get the Nobel Prize because we don’t know yet how to define cirrhosis. And #2 is, however, if the tumor is now 5 cm, the LI-RAD 5 kind of, you know, ability to get the accuracy will drop all the way to 60, 70%. My question is any of us are ready to go and sit down at the polls and say this is HCC and I swear by the LI-RAD 5. I’m not sure we can do that. We need to show diagnosis.

Case: A woman in her late 70s receiving adjuvant anastrozole for Stage I breast cancer who is now receiving atezolizumab/bevacizumab for metastatic HCC — Sunil Gandhi, MD

DR LOVE: So here’s another case. A 79-year-old woman with a history of breast cancer, shows up on surveillance, actually, with a liver lesion. He thought it was a met, but it wasn’t. Here’s the case.

DR GANDHI: This is an interesting patient. 79-year-old female. She had a Stage I breast cancer, and she was just on anastrozole. I know that ASCO recommends against doing the tumor markers, but I have had some good experience, so I usually follow CEA, and this patient’s CEA went up to 10. So I did a CAT scan and there was 3.2 cm liver mass. And we biopsied it. I thought I may be a breast carcinoma with liver met; it turned out to be hepatocellular. AFP was negative. So I sent even to Shands for second opinion on biopsy. It is definitely hepatocellular.

Her performance status is good, so I am going with atezo plus bevacizumab kind of treatment. Is that standard? I did give RFA to this patient because it was 1 spot. But there were multiple intrathoracic lymph nodes, too. I did not biopsy those lymph nodes but presumed them malignant when the liver mass is there. So, that’s why I thought that I should give some treatment to this patient.

DR LOVE: Yeah. You kind of have to grab them away from the interventional radiologists to treat them. Any thoughts about that case?

DR ABOU-ALFA: Thanks so much, Dr Gandhi. So 2 points. Number 1, I 100% agree with you. And this is absolutely right. As we both know, and humbly, it’s not like I’m an expert in breast cancer. But Stage I breast cancer, as we know, breast cancer is a disease that people live with. It’s not like people die from. So by all means, you are absolutely right to really focus here on the HCC.

Number 2, the RFA is actually a curative approach. If it was really an assessment for curative intent, I can understand. However, you brought in a little bit of lymph nodes later on. So you’re right, systemic therapy would be appropriate. I will say that within the confines that you need systemic therapy, atezo/bev because it’s the first line standard of care therapy which is already approved, by all means, is an appropriate option. There’s not really anything wrong with that.

Case: A man in his late 70s with metastatic HCC and portal vein thrombosis receiving atezolizumab/bevacizumab (NGS [next-generation sequencing] with PIK3CA mutation, PD-L1 50%) — Susmitha Apuri, MD

DR LOVE: All right. Let’s do one more case. This is a 79-year-old man, a patient of Dr Apuri. This patient actually developed portal vein thrombosis on atezo/bev. Here’s the case.

DR APURI: Did very well initially, but he developed progressive abdominal pain and a lot of fatigue and nausea. A repeat CT demonstrated a portal vein thrombosis, and he was started on anticoagulation with apixaban. I had to discontinue his treatment because he was reporting a poor quality of life. He started having progressive increase in his alpha-fetoprotein level. We started him on lenvatinib. Unfortunately he tolerated the medication very poorly. He developed ascites. I thought he was progressing. His AFP was rising. I got the results of the solid tumor NGS, which did show a PD-L1 of 50%. And he was also PIK3CA positive. He’s on cabozantinib right now.

Would he be a candidate for pembrolizumab? Is there any role for alpelisib and fulvestrant? We are looking at somebody who currently has an ECOG of 0. He’s back to his woodworking. Every time he walks in he says I feel great, don’t take me off of the cabozantinib. I would love to know if he would be a candidate for ipi/nivo. Would he be a candidate for radioembolization even though it’s going to be probably like 50% of the tumor.

DR LOVE: Any thoughts about this? And she brings up also the PIK3. For breast cancer, they use alpelisib and fulvestrant. I don’t know if that’s ever been done with HCC. Any thoughts about this case?

DR ABOU-ALFA: Yeah. Thanks so much, Dr Apuri. Very important points. I’ll try to cover as much as I can. If I forget one point, I’m sure Dr Love will remind me. Number 1, I respectfully disagree with you on the anticoagulation. And I’m glad that you stopped it because there’s no data at all if you have portal vein thrombosis, anticoagulation is going to matter at all. If anything, data has shown that it really does not pose people at any further risk. And it’s routine for us that patients with PVT we don’t really anticoagulate at all.

Number 2, in regard to choice of therapy, because we kind of alluded to that, is #1, is, let’s say, if everything is available, would you do atezo/bev or you say because it’s PVT, definitely atezo/bev and not necessarily the durva/treme because of the PVT? Not necessarily. Actually, because remember, the portal vein thrombosis, when it comes to B4 level, all those patients are not even treatable probably. It’s probably Child-Pugh B7, B8, B9. So it’s not necessarily that patient is like doing extremely well in that regard.

With this said, is the choice of lenvatinib that you said did poorly? You bring a very important point here that actually Dr Love and I were talking about before starting the program. Please, please, I urge everybody to make sure that when a patient is on one of those TKIs, check on them very regularly and very often. Interestingly, our routine in clinic at Sloan Kettering, if a patient starts on lenvatinib, we give a call after 3 days. How are you doing? How’s everything going? Do you want to show me? Now, of course, all of us have videos and what have we. We can even look at hands and see how things are and see how their mobility is. And #2 is you see them again in-person in one week. Don’t please just give the drug and just see them in a month, per se. I’m actually positively surprised and I’m happy to see that people did very well on cabozantinib, your patient, because the same kind of thing. Definitely to your credit, you clearly have been managing the patient appropriately well and close monitoring of that situation enough that the patient was able to continue to keep working, et cetera. Sadly, sometimes we hear people saying, I remember, we led the cabozantinib study. We have a lot of hands-on experience with it since it was published in the New England. And we said clearly that close monitoring, adjustment of dose if necessary from 60 mg to 40, by all means, is an option for you. Same like with lenvatinib from 12 to 8 mg. So I’m happy that you kind of went through a very appropriate regimen sequence.

Now your question in regard to the checkpoint inhibitors. Why not? If anything, the pembrolizumab is already approved in second line therapy. And after all, there’s not necessarily any contraindication for that purpose. And at the same time, as we spoke a little bit earlier, we have a little bit of laxity in regard to what you call line 2, line 3, line 4, as long as we get exposure to all the options of therapy for the patients. The ipi/nivo, I would say I’m a little bit relatively cautious about because actually of the concern about the adverse events which I think has been reported quite a bit historically in regard to the repeated dosing of the ipi as we know with the anti-CTLA-4.

Management of Biliary Tract Cancers

DR LOVE: All right. Well let’s talk about biliary tract cancers. And I’m going to go through some cases there as well. But also, I want to get into this paper, the TOPAZ-1 paper. I had the pleasure of working with Dr Valle and we did the program that we were talking about earlier. So interesting. I learned so much from that. What are your thoughts about this study? I know very different kind of considerations than what we were just talking about with HIMALAYA. Globally, it looks like there was a modest improvement by adding durvalumab. It doesn’t look like there was a huge downside other than financial, et cetera. Any thoughts about this study? Even though it’s a modest step forward, is it enough to come into practice? Is this your preferred first line approach at this point?

DR ABOU-ALFA: I was beyond delighted to see that study. And I would probably to summarize that say, wow. It’s very impressive. And it’s definitely a very positive study. Yes, you are right. Probably, the magnitude is not really what we aspire for. But remember, we can have very high aspirations nowadays. But this is still beneficial for patients. There was clearly an improvement. At the same time, it’s very important, it brought for the first time because interestingly, and I’m sure Dr Valle told you, that in the UK, they limit the therapy with gem/cis only for 6 months. And interestingly, the TOPAZ-1 was done based on the ABC-02 study of Dr Valle and colleagues in the UK. In anything, they limited the chemotherapy only to 6 months. For the first time, probably rather than treating up to toxicity or until progression, we probably can visit the idea if people are doing acceptably well, stop the chemotherapy at 6 months and continue on durva alone. And I have to say, because remember, this is exactly the time, the study is exactly, I’m just calculating, it’s about like exactly 6 months plus 14 days or so. And we started the first patient, it was published or reported on the 21st of January, because I remember that day because it’s the same day that I presented the HIMALAYA. But if anything, already we started the first patient, this was on Friday. The first patient started on that therapy was on Monday. And if anything, in other words, yes, I had patients already stop the 6 months of chemotherapy and now only on durvalumab. I don’t have any more than that to say at this point in time. But I will say so far, so good.

Funny enough that the most important challenge that I have seen on that regimen is to try to convince patients to come to clinic. They are doing amazingly well clinically, enough that they are traveling and everybody is back after the COVID pandemic, a little bit more lax on traveling and I have to really beg them to come and get the therapy. I would say, this definitely is going to have its clear stand in regard to the treatment and is going to become the standard of care, if not it is already the standard of care for patients with biliary cancer in first line treatment.

DR LOVE: And as you can see here, the hazard rate in terms of survival is 0.8. It’d be great if it was better, but still, those curves are separate and the tail, at least at this point, looks maybe interesting. No subset that doesn’t seem to benefit. I think adverse events. And we’re using so much chemo/IO nowadays. Everybody knows kind of what’s involved.

DR ABOU-ALFA: Yeah. And then, one important point —

DR LOVE: I want to get through some cases. Anything else you want to comment on?

DR ABOU-ALFA: Yeah, absolutely.

DR LOVE: Go ahead.

DR ABOU-ALFA: One point about the survival. You hit it right now. We please have to remember that after all, this study is gem/cis versus gem/cis only until the T-cells are primed to do the separation later on in the curve. And as such, I’m not surprised the hazard ratio is 0.8. But if you look at the curve, you will see that the separation really happened after the median. And that’s very important to remember, that this kind of priming with T-cells takes a little bit of time. So no doubt that this is still a positive study and definitely is the right therapy to give.

DR LOVE: Interesting.

Case: A man in his late 50s with resected Stage IIB gallbladder cancer s/p adjuvant capecitabine who now has metastatic disease (HER2-positive; MSS, PD-L10) — Nasfat Shehadeh, MD

DR LOVE: All right. Let’s go through some cases. And actually, this first case brought up something that I thought was one of the most interesting things that Dr Valle talked to me about last week. And I’ll get to that in a second. Kind of a big surprise, but not really which was T-DXd. You’ve heard about that one, I’m sure. Incidentally, the HER2-low paper was just published today in the New England Journal. Sara Tolaney from Dana-Farber did the editorial if you want to check it out. Anyhow. This is a 57-year-old man, initially resected and was hoped to be cured with surgery, got adjuvant capecitabine, but now has metastatic disease and was found to be HER2 positive interestingly enough. Here’s the case.

DR SHEHADEH: Cholecystectomy, young, healthy guy, incidental bladder cancer, had further resection done, which showed Stage T2b, but nodes negative. He received 6 months of capecitabine, according to the guidelines. A CT scan a month later was completely negative. Then later on, surveillance CT scan had unfortunately liver lesions, 22 mm, biopsy consistent with recurrent gallbladder cancer. His PET scan showed also multiple lymph nodes in the porta hepatis. Discussed his case in the tumor board. He’s not resectable. And we did NGS on him, and unfortunately, we didn’t see a lot of alterations that we could target down the road. So I just started him on cisplatin/gemcitabine.

A couple of questions. Patients who have high-risk gallbladder cancer, are we still considering the single-agent capecitabine is the standard of care? Should we use 2 agents? And when you have Stage IV disease, what is your best option for these patients in the context of absence of targetable mutations?

DR LOVE: Have you had any patients who had targetable mutations with cholangiocarcinoma?

DR SHEHADEH: Yeah, I have recently. I actually have one who has cholangio with HER2, and I’m treating him with — we had difficulty by insurance, but eventually approved his chemo with trastuzumab. And he’s actually doing relatively well. He responded to treatment, and he’s still receiving.

DR LOVE: Sorry, that was the other patient who got the ToGA regimen. In any event, I just want to comment. We’ve seen data from the MyPathway study looking at pertuzumab and trastuzumab. We bring this up when we talk, you know, of course, your colleague, Dr Janjigian, we talk with all the time about HER2 positive upper GI cancers, T-DXd.

This is what I wanted to ask you about. This is what surprised me. I didn’t realize this was presented, the HERB trial of T-DXd in biliary, not only HER2 positive, but HER2-low disease that they just presented. And the bottom line is, there’s the waterfall plot, but they had 6 patients with PRs who were HER2 positive, 6 out of 22. And they had 1 patient out of 8 who was HER2-low who had a PR. So it’s only 1 case, but interesting. So any thoughts about this? If you have somebody who is running out of options, would you try to get T-DXd?

DR ABOU-ALFA: By all means, if there is a HER2 alteration like as we see over here, independent of the expression, by all means, it’s very much worth it because we know very well gallbladder cancer especially has a certain marriage in regard to the HER2 alterations. Interestingly, we see some of it in cholangiocarcinoma as well. And as such, please, please, it’s very important. All aside joking to say, when a patient with biliary cancer happens, even before they knock on the door of your clinic, they should have their next generation sequencing happening already. Because you might be surprised how many patients you can offer certain therapy for. For the OPAL study, by all means, we’re all very happy with that. And we saw it all at ASCO several weeks ago now. And no doubt that on one hand, we were happily surprised to see the response rate, but also at the same time, there was a clear acknowledgment in regard to pneumonitis which did occur which we know of the class of drugs that it can occur with.

DR LOVE: And my colleagues corrected me. It was actually Sara Hurvitz, not Sara Tolaney who wrote the New England Journal editorial. So yeah, you mentioned about ILD, interstitial lung disease. Of course, we talk about that not just in breast, but lung and upper GI. And they actually had several cases of ILD. I think they had 2 deaths. So any thoughts about, for practical purposes, whether you think this is a reasonable strategy or do we need more data?

DR ABOU-ALFA: I will say, we still need more data. But, however, I will say still, a patient with HER2 should at least have access to one of the clinical trials. And there’s plenty of them. We definitely have a lot of interest, being either by sponsors or by the academic field. So please always, and I’m sure not only us, but all of our colleagues, please reach out. You’ll always be surprised. You always will find some clinical trial closer to you that you can offer to the patient to jump on. I would not necessarily always vouch to just give them any of the therapy because otherwise, we’ll never learn anything. We have to do them on clinical trials so we can really finally get an answer. As I mentioned to you, Neil, I’m afraid that the depth of the HER2 understanding in biliary is not that thick. But at the same time, the spread or the width is very big. And that’s why we need to really strengthen on that depth to make sure that we have robust data that we can depend on.

DR LOVE: In the ASCO HER2-low plenary session, Dr LoRusso was commenting on HER2 mutations which you see a lot of in lung cancer. The lung docs want to use it first line in these people with mutations. Do you see HER2 mutations in biliary tract disease?

DR ABOU-ALFA: We’ve seen it, but not necessarily that we knew how to interpret better or different from anybody else. But no doubt, that’s why, again, one more time, please, same as we said in HCC, in biliary, biopsies and next generation sequencing is very important so we can learn and really understand those patterns correctly. And this way, we can probably defend or not in regard to whether you treat them first with first line or not.

DR LOVE: And your point about clinical trials is so important because in the past, a lot of times clinical trials really didn’t benefit the patient, chemo A versus chemo B. Nowadays, we have so many exciting agents. Here’s one too, zanidatamab. I can’t pronounce it. We’re hearing about all kinds of bispecifics in hematologic cancers and now in solid tumors. So a lot of opportunities. We saw some data actually with the agent. Any thoughts about this bispecific anti-HER? I don’t even know if they looked at it in breast cancer. Do you know anything about it?

DR ABOU-ALFA: So we know that it has a certain efficacy, but to be fair, it was not compared yet to anything else. So we can’t really claim more than it is a bispecific, i.e., it probably has a certain advantage. But no doubt, first analysis will be needed. I doubt that we’re going to have ultimately a comparator work over here because I think there’s certain particularity for each one of those therapies. If anything, it will be more valuable to understand even mathematically what is the sequence of the therapies that patients get. Maybe we’ll conclude something out of it. As I mentioned to you, and maybe we can talk about that in the FGFR2, I would say that the alterations are not really random alterations. They are happening because of a certain deterministic effect. And as such, if we analyze more data mathematically, we’ll be able to pull out more understanding about what should be first, what should be second, what should be third line, even interestingly, as you and I know, about maybe to recycle certain therapy and give them again for patients.

DR LOVE: Yeah. Dr Abou-Alfa was telling me about this determination concept he has. We could spend a whole hour just talking about that. Anyhow. In the chat room, Swatti has a 52-year-old patient with intrahepatic cholangio progressing on gem/cis, has an IDH1 mutation. Wants to know is okay to use ivosidenib second line? I would also ask what about ivosidenib first line? And we’re about to see a case with IDH2. But first, any thoughts about this case with IDH1? Would that be typically second line or what about first line?

DR ABOU-ALFA: Sure. So the question is, yes, correct. This is, ivosidenib, is second line therapy, as I presented it, you remember, at the plenary in ESMO, wow, 2019 already. And it already was published. So no doubt, it is a second line therapy. Interestingly, in the patient that you just presented, you can also do uncertain challenge. It depends on what the progression was. Would you keep the gem/cis and add durva and see what happens? Because this could be a very important strengthening of the scaffold before you come to the ivosidenib. But the ivosidenib is totally correct in regard to second choice therapy.

Now in regard to your question, Dr Love, in regard to what about first line? That’s very interesting because we all thought, everyone wants to be at the front of the bus, but out of nowhere, we have the TOPAZ that came in and changed the whole scene altogether. Would I say that maybe it will be worth it one day to understand that maybe TKIs and targeted therapy first line followed by the checkpoint inhibitors plus chemotherapy as second line? I’m not sure we’re going to answer those questions because they are not necessarily a self-interest for every sponsor. But, however, at this point in time, based on the data that we have, the first line therapy is gem/cis/durvalumab and then you do the targeted therapy afterwards based on the effect of whatever genetic alterations you have.

Case: A woman in her early 40s with a history of ductal carcinoma in situ and family history of breast cancer, now with metastatic cholangiocarcinoma (NGS with IDH2 mutation) — Joanna Metzner-Sadurski, MD

DR LOVE: So let’s get into another case, again, related. And we’ll see what you have to say about IDH2 but also, the way this patient presented. A young woman, 43 years old. Here’s the case.

DR METZNER-SADURSKI: My patient presented last year with bilirubin of 15, and she was in the hospital, and she has liver masses. She was 43 years old. We did biopsy, and it was cholangiocarcinoma. And she was deteriorating, so I decided to give her gemcitabine. And she responded to gemcitabine. Her bilirubin dropped to 8. They put a stent. We continued gemcitabine and added cisplatin. She had response, but unfortunately she progressed. FoundationOne came back positive for IDH2.

Would it be an option for her to consider IDH2 blocker for biliary carcinoma? And then also with such a history of the whole family having cancer, we haven’t found a mutation, would it be an option of olaparib, a PARP inhibitor, for this family, knowing that there is something, we just don’t know what it is?

DR LOVE: Yeah, I should have mentioned, she has an extensive family history, but germline testing is negative. Anyhow. Any thoughts about this case?

DR ABOU-ALFA: Wonderful case. If anything, number 1, in regard to the IDH2. Yes, it can occur. We have to know more details because, as we know, all of us, enasidenib is definitely a therapy for IDH2 but, however, it only targets for specific alterations in AML. I can pull them out to remember, but I recall very well, for example, the R140Q and R172K. Interestingly, cholangiocarcinoma has R172W which is not the one that probably will benefit from enasidenib. So it all depends on the genetic alteration. I strongly recommend that please look into the specific alteration and see if it really will benefit from the enasidenib or not.

The point number 2, quite fascinating to bring in the genetic alteration, or potential genetic alteration in a family where we don’t see any. Remember, we don’t see any based on what we look, or where we look. Because it all depends how we expand further our portfolio. This is a very touchy subject for us. I would say probably, we did it in the quiet. Really, we didn’t talk much about it. But we actually invited 72 physicians last January from 40 countries that are in conflict. In other words, these countries are either at war or they have certain conflict in and of there are separation divergence of population and sometimes even conversions of population. And we looked at to start studying if we can assess genetic alterations that are based on how you diverge a population or converge them to see if we can discover more genetic alterations. More work to come on that. Stay tuned.

DR LOVE: So interesting. So one final case. Actually, there’s a bunch of cases coming into the chat room. Let’s do at least one of them. So a 56-year-old woman, cholangio Stage IV, FGFR fusion. That’s what I was going to talk about next anyhow. Post-chemotherapy with progression. Pemigatinib given. Good response for 2 years. Now disease progression. What about futibatinib in this patient? What a great case. And also, another question he has. Any data on FGFR amplification?

DR ABOU-ALFA: Sure. Two wonderful questions. So point #1 is exactly the subject that you were just touching on. And maybe it’s pertinent to really grab a minute or less about that. I would ask my colleagues to look at a beach scene, as I describe it. And if you look at the arial view of a beach, you can see people hanging around on the beach and say, you know what, they are sitting there by random. Well guess what? We call it by random only because we don’t why they are on the beach. Because interestingly, if you were to really look at the people who are sitting closer to the water and you go, let’s say, talk to them and they tell you, we’re close to the water because we like to swim. Then you can draw a rectangle across and now you have a little bit of a more kind of like not a random presence, but really a very well delineated presence. If you look at the umbrellas together that are really like big families and they’re sitting closer all the way in the back of the beach closer to where the restaurants are and the facilities are and you draw another rectangle, that really will take away that randomness. And then the couples that are just coming to hang out. They care less where they are. If you put a vertical line through, interestingly, out of nowhere, your random beach scene is not anymore random. This is exactly what happened in regard to FGFR2. If anything, the pemigatinib progression, it means a certain genetic blockade or alteration did occur that will require different therapy. Sadly, we don’t know which one it is. You kind of are doing by whatever is available. If futibatinib is the next one, for sure. Why not? But ultimately, we’re working with mathematicians to understand before a genetic alteration to see how well we can delineate which one to use because as we joke, and this is quite fascinating, Einstein always said, God does not play dice with nature. If anything, it’s deterministic. This is really what I was trying to explain to convince Dr Love about.

DR LOVE: Yeah. And this is the way I like to hear my translational medicine, with the beach analogy. But just to sort of finish out about this. I see another case in the chat room real quick because it’s a very common issue. I’ve heard a bunch of cases like this. Daniel has a 67-year-old woman, metastatic cholangio, status post everything, cis, gem, bev, FOLFOX, FOLFIRI, durva/treme on a clinical trial, no targetable alterations, MS stable. Anything out there that you know or palliative care? Trials?

DR ABOU-ALFA: If performance is permissive, of course, clinical trials. And there’s a lot of opportunities there. Remember, clinical trials are not anymore about just the toxic chemotherapeutic intervention. There could be always some opportunities. And as we have published a long time ago, the potential for response it close to 20%, clinical trials in regard to Phase I studies. So please, by all means, definitely reach out for clinical trials.

DR LOVE: So give me an example of a trial you have at Memorial that you could put a patient like this on.

DR ABOU-ALFA: I would say plenty. But, for example, certain different alterations of the checkpoint inhibitors, novel different checkpoint inhibitors like LAG-3, et cetera. And on and on. And if anything, we just opened a study which is already ongoing for the, it was just published as you and I know at the World GI — sorry, at the ESMO GI or the World GI in Barcelona last week, on the AGN1181 plus balstilimab. And this is run as a Phase I on all diseases. We proudly were able to get a cohort for familial carcinoma. And we’re very proud of that because always this is a very big challenge for us to explain to sponsors how critical it is for a super rare disease with familial carcinoma. There’s only 200 patients worldwide. They have a clinical trial. We are very happy that we started already the first patient on the therapy. And hopefully, so far, so good.

DR LOVE: So one final question then we’re really going to stop here. I think a lot of people will know that one of my favorite agents is pirtobrutinib in CLL, a covalent BTK inhibitor where you see responses to people who have progressed on noncovalent BTKs like acalabrutinib, ibrutinib. Well it turns out, I didn’t know this until we talked to Dr Valle, that one of these FGFRs is also, I guess, irreversible and is a co — no, not — covalent. That’s futibatinib. And you actually can see responses related to this case that was presented of the patient that had a response to 2 years of pemigatinib. So is it a completely different mechanism? And do you see responses? Would it be rational to give futibatinib in this patient who had pemigatinib?

DR ABOU-ALFA: So by all means, you’re right. The double covalency and, at the same time, its irreversibility can be a plus. But, however, we’re not really sure where it does position itself. You already kind of also mentioned, and I think it was in one of the cases, about mutations in regard to FGFR2. By all means, all those therapies will kind of ultimately need to be tested or looked into. However, as I said, please, please, this is an invitation for everybody. We need to do this all together. If we really can tell from the analyses of blood with FGFR testing before and after therapy, no matter what it is, I think we’ll be able to get a little bit of better clarity about what will be first, second, third, et cetera, line.

DR LOVE: So, Ghassan, thank you so much for working with us today. I think when I go out on the beach here in Miami this weekend, I’m going to be thinking about your beach analogy. And, audience, thank you for attending. Come on back next Tuesday. We’ll see what Dr Klempner has to say about upper GI cancers. Be safe, stay well and have a great day. Thanks so much, Ghassan.

DR ABOU-ALFA: Thank you so much, Neil, for having me. Thanks, everybody, for listening and thank you.