Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we talk about key papers and presentations over the past year in hepatobiliary cancers.

We have a great faculty today: Prof Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center in New York City and Dr Richard Finn from the David Geffen School of Medicine at UCLA in Los Angeles, California.

As always, if you have any questions or cases you’d like to run by our faculty, just type them into the chat room. We’ll talk about as many of these as we have time.

As always, we have a very brief pre-and post-meeting survey. If you take that survey we’ll learn a little bit about you, and you’ll get a lot more out of this meeting.

If you’re into audio programs, we know a lot of people end up listening to our webinars in their cars when they’re driving around, check out our program with Professor Arndt Vogel on the management of HCC.

We do webinars all the time. On May the 17^th we’ll be working with Joyce O’Shaughnessy talking about HER2-positive metastatic breast cancer. And Michael Overrman from MD Anderson will talk about colorectal cancer on May 18^th. On the 23^rd we’ll be doing a program on soft tissue sarcomas and related connective tissue disorders. Haven’t touched on that topic lately. Really looking forward to it. And then of course our annual visit to ASCO in June at the Hilton Hotel. We’re doing I think 10 seminars. Check these out. They’re also going to be put out live online.

But today we’re here to talk about hepatobiliary cancers and particularly what’s happened over the past year. As we do with all of our Year in Review programs I meet separately with each faculty member to record a presentation and discussion about the presentation, covering a lot of papers. There are links to that in the chat room, and we’ll also send that out again when we send out the link to this webinar.

So for a comprehensive review of all the papers we’re talking about, check out these 2 presentations. But then what we like to do is then sit down with the faculty and pick out some of the most interesting presentations and topics and get the other faculty person’s take, talk a little bit about clinical implications.

But here are all the papers that Ghassan talked about. We’re just going to, again, review the top line. Same thing with Rich’s papers on biliary tract.

So we’re going to spend our time really talking about papers there.

Prologue: Last Week

DR LOVE: But I’ve just got to tell a little story before we get started. This is not hepatobiliary, but it’s just, I don’t know, something happened to me last week that I just want to share. I was telling Rich about it before you got here, Ghassan.

So 3 or 4 times a year we get into the situation where we’re doing a whole bunch of things, like 1 is the ONS meeting (Oncology Nursing Society). So we went there last week. We actually amazingly did 10 programs in like 4 days. It was like really crazy and wild. And then from there we went to AUA in Chicago. That was in San Antonio. We did 2 meetings there. And I’m still kind of almost recovering from this crazy experience.

But there was something that happened last Saturday that I keep thinking about, and it happened at the AUA Meeting. And our audience today is mainly general medical oncologists, and all I can say is there’s a paper called the EMBARK study, a Phase III study in M0 prostate cancer. We’re doing an ASCO Meeting on Saturday night, June the 3rd, on prostate, so we’ll talk about it there.

But I was completely blown away by this study. That’s all I’m going to say. I think this study from a quality-of-life point of view is amazing, what they saw. I think general medical oncologists are going to see it differently than the urologists did, because we did a whole program there, and the urologists didn’t realize what we were interested in. And I’m just going to summarize it by saying — and Rich, you have also a very heavy background, you see breast cancer patients. I’m going to say I’m wondering once people really take a good look at this study whether they’re going to conclude that enzalutamide maybe is going to be the new tamoxifen. To be continued. I just can’t get it out of my head.

But it also brings in the issue of the way general medical oncologists see data, and I think that’s actually relevant to some of the things we’re going to talk about. So I just want to put it out there that in my mind a lot right now, EMBARK.

Hepatocellular Carcinoma

DR LOVE: All right. HCC. And if you want to see what it’s like to be a general medical oncologist, so many approvals and new papers coming out, between the time that I met with Ghassan, which was just a couple weeks ago, and now, there was actually a very important paper presented. It was at the AACR Meeting. All we had at that point, Ghassan, was the press release, and you and I talked about it, but now we saw the data. Bottom line, positive adjuvant study of atezo/bev. And we’re just going to comment on it.

Also, Ghassan during his talk talked about the update to the BCLC algorithm. I want to bring that up, as well, because now there’s a paper that just got published. I’m curious how that fits in.

And finally I just want to ask you about another paper related to antibiotics and IOs, but here’s the IMbrave050, adjuvant atezo in patients who’ve been resected or ablated. Of course they’re not going to look at transplant because an IO in transplant doesn’t work.

I guess one thing that was interesting, Rich maybe you want to comment on it, that they brought out in the presentation that I wasn’t aware of was the so-called bimodal distribution of recurrence, although I don’t know how much that second one is recurrence or primaries. But any comment on that, Rich?

DR FINN: Yeah. Liver cancer is developing in a premalignant organ. The whole liver should be considered premalignant because it’s been exposed to some insult, hepatitis B, hepatitis C, alcohol, et cetera. And we know that for the patients who are resected that we can see recurrences, and this is somewhat arbitrary, we say within the first 2 years, that this is probably a recurrence of the tumor that was resected, and there was micrometastatic disease within the liver. But then there’s a group of patients who recur years later, and it’s those patients who we sense are just de novo, new metastatic — de novo new cancers, and that is why transplant is an attractive approach for patients who can’t have resection because it takes out the bad soil.

DR LOVE: So Ghassan, in the chat room Dr KS Kumar, who’s from the Florida Cancer Specialists, I’m sure he was waiting for this so he could ask this question, says he just saw a patient, poorly differentiated HCC, yesterday, 14 x 9 x 5 cm tumor that was resected, no mets. He wants to know based on — he wants to give atezo/bev. So he wants to know how long does he wait to start the bev. The patient has no cirrhosis. Does she need EGD?

So just keep that case in mind, and let’s just take a quick look at the data. This is I guess part of their background where they talked about I guess the recurrence over a period of time based on initial stage.

But here’s the bottom line. There was a DFS — RFS advantage, hazard rate 0.72. It kind of reminds me we’re talking about the first-line POLARIX trial in diffuse large B-cell, a hazard rate, no survival data there. That got approved by the FDA. Completely different cancer.

But anyhow, survival at this point — you look at the subsets. I’m not sure there are enough patients there to really talk about whether etiology is any different. Everything seems to be mainly over to the left. Maybe you all can comment on that. Survival data immature at this point. So you’ve got relapse-free survival with a pretty good hazard rate. I’ve seen better so to speak.

So bottom line, Ghassan. First of all, is this something you want to do? Would you like to see the FDA approval? And what do you think about Dr Kumar’s patient?

PROF ABOU-ALFA: Thanks so much, Neil. I think point number 1 is no doubt independent of the nitty gritty details that we’re going to go through. This is of course good news for patients because no doubt for the first time we’re seeing at least a suggestion of some improvement in outcome based on a reduction in risk free — recurrence-free survival.

On the other hand, a very important point is does the biology make sense to really use checkpoint inhibitors to prevent cancer from recurrence. Interestingly it does, which interestingly we could not see with the tyrosine kinase inhibitors like sorafenib, and it failed beforehand. But now for the first time at least we have just like something that might be working in regard to the checkpoint inhibitors. Why is that? Because clearly the insult of the surgery does make a serious alteration in regard to the immune microenvironment, enough that an alteration of the lymphocyte/neutrophil ratio will probably be there, and as such could be that the checkpoint inhibitor is coming to the rescue in that regard.

I add to this of course what Rich mentioned, which is like it’s a precancer to begin with, so there’s no doubt this kind of adjuvant therapy that we’re doing is not suddenly only handling what could be erupted from the tumor resection but could be what’s already there to begin with, and as such all in all biologically it does make sense.

However, when we look at the data, and to be fair, these are the 2 messages. So number 1 is this is all in abstract format so far, and already I had the chance to talk with actually Dr Chow Pierce, and we chatted about the data, and to be fair, this needs to really come up to the final — exactly the details, as we just heard from you and from Rich in regard to that double recurrence pattern, as you said, the immaturity of the full data in regard to the recurrence. Even though the suggestion, if we look at the Kaplan-Meier curve, and you are already basically trained in how to look at Kaplan-Meier curves, they look good. We can insert fingers between the 2 arms, so why not? But we have to wait for the final data.

And on top of that, of course, we need the approval. Yes, the drugs are available, but we really have to make sure that we see the FDA looking into that data from perspective of yes it does make sense or does not make sense.

So I would say yes, what we are seeing so far is probably okay, but we probably have to wait for a little bit more information before — to move on to make it the standard of care.

In regard to the endoscopies, by all means, because remember, patients can be at risk, and no doubt the endoscopy will be appropriate. What is the timing for that? As usual. It’s got to be probably within a month or so, and we will look into the information of this study in detail once we see it.

DR LOVE: Rich, what’s your take? Is this a therapy you want to use? I think you told me you’re trying to use it on somebody. I don’t know if you can access it. Interesting that the control arm by 18 months they’ve got like more than 50% recurrence, so it’s not a great prognostic situation. Is this something you want to do, Rich?

DR FINN: Yeah, for sure, especially for someone who meets the trial entry criteria. I had a patient, poorly differentiated 8 cm tumor. He was very motivated to try this. And Dr Kumar’s patient, you could even argue that patient could have gotten atezo/bev up front. A large tumor, borderline, BCLC-B or -C, and this will relate to the new classification — or not the new — the new comments on the Barcelona system. But a large tumor like that in a symptomatic patient, the odds of them being cured with surgery alone is very low, and I think I would give them every benefit of the doubt based on the data we’ve seen from the 050 study to give them the option of getting the regimen. And the study did require endoscopy, so that should be done.

DR LOVE: So Ghassan, you talked in your presentation about the BCLC revision. I guess this is the first revision since 2018. This paper’s like 30 pages long. It’s got a ton of stuff. Just this diagram itself I can’t even begin to understand. You go into a lot of that in your talk, but they were talking about all of the things that happened since 2018, and here it is now, an adjuvant study came on after they published the paper, so now they’ve maybe got to revise it again. But anyhow, any way you could translate this for somebody who doesn’t want to read all 25 pages of this thing, Ghassan?

PROF ABOU-ALFA: Absolutely. So IMbrave — the BCLC is a very interesting system that really dates back for quite a while, for more than 20 years. That stands for the Barcelona Cancer of the Liver Clinic, which is a clinic that really takes care of liver cancer. I give a lot of credit for Dr Jordi Bruix who really started all of that effort beforehand.

The idea was to try to stage the patients based on the extent of cancer, but at the same time, because of the simplicity of the process at that time because of the sadly not that many therapies available, it also offered what do you do. It became like a manual. You have this, you do that. You have that, you do this. That’s pretty much what the BCLC was about.

Historically, always there was the statement which was quite fascinating that the BCLC does extremely well to the extreme left, ie, on the left of the screen you can see the early stage disease. You see all of those kind of arrows and details and what have we. As always what you say, the BCLC does very well on the left but does very poorly on the right.

Now as time evolved, and there’s more therapies have really been brought into the advanced disease, which is what Rich and I have been heavily involved in, and many other colleagues, at the same time a better understanding of the intermediate stage, interestingly things start evolving to more details in regard to the intermediate stage and in regard to the advanced stage.

As such, there are a lot of notions that are brought in, and Rich already brought up one of them. He said like Dr Kumar’s like did really have to have surgery, and as such we’re now reading things a bit in more detail. What are we dealing with.

To give an example, and this is between parenthesis to explain the BCLC, Dr Kuda from Japan made an argument. He said based on the number of lesions in the liver, size of the largest lesion in the liver, and these are 2 numbers that are straightforward to do, 4 cm largest lesion, 4, plus 4, number of lesions. Let’s say 4 plus 4 equals 8. Is that number more than 7? Local therapy does not work. It should be systemic therapy.

As such, it’s very nice, he did an incredible job. Really I’m very fascinated with that data because it really for the first time if we go back to see it you’ll see that there are 3 prongs that fall from the intermediate stage, and 1 of them interestingly directly from intermediate stage all the way to advanced therapy. So that’s the notion of understanding the disease better from how much it’s really implicated in regard to where does it stand, what does it imply in regard to recurrence, et cetera.

As such, I would like to say is why we steal patients from each other like for local therapy, systemic therapy? Absolutely not. It’s an invitation for us to make sure that we always look on tumor boards, multidisciplinary team approach, is a critical component for HCC. Everybody’s got to be on the table.

And here because we are only talking mainly to our colleagues in oncology sadly I have seen over time, I do mean really floating all around doing this for the last more than 2 decades, sadly our medical oncologists are the least people to go to the tumor boards. Please be there, because otherwise guess what? Our colleagues don’t know what you’re doing in regard to atezo/bev and durva/treme or what have we, and do you know what they’re going to offer? They’re going to offer hospice care. So that’s why it’s very important for us to be there.

DR LOVE: Well the other thing that they’re going to off is intrahepatic therapy, and I hear oncologists saying maybe, Rich, so much intrahepatic therapy by the time they see the patient the patient has very poor liver function. And thinking, again, about the guidelines that have been out there, before we started to see IOs we didn’t really see responses. Now we have atezo/bev, durvalumab/treme, where you see responses. Rich, is it your take that maybe we’re using systemic therapy earlier now and intrahepatic-directed therapy a little bit less often or not really because like Ghassan says the oncologists aren’t at the tumor boards?

DR FINN: I think that’s definitely very correct that oncologists do need to take a bigger role in the decision making early on because we do have many more options, even before immunotherapy we had sequential TKIs and ramucirumab, and that’s only been more important now that we have IO, which is markedly changing the natural history. And that is the new rendition of the BCLC that I think is relevant, is that it recognizes that some patients with intermediate disease might be better off with systemic treatment than locoregional treatment. And if a patient only sees 1 specialist they’re going to get an opinion based on that 1 specialist, and it really behooves us to work together as a team, as Ghassan highlighted.

And the other thing about the BCLC is patients are moving. Some patients are intermediate, they have a great response to locoregional treatment or potentially even immunotherapy, and maybe they’ll be resection candidates in the future. It’s not a one-way street, and the new iteration of the BCLC recognizes that staging can be somewhat fluid.

DR LOVE: Well, another thought, Ghassan, would be instead of either intrahepatic or systemic how about both. And actually Hassan in the chat room is curious about I guess a study looking at TACE and SBRT followed by avelumab, I don’t know this paper, but anyhow a high CR rate, 43%. What about this idea of combining, particularly SBRT? We have this great study in non-small cell lung where they use IO, durvalumab, after chemoradiation, so nobody knows for sure how much synergy was there. Any thoughts about synergy between like TACE, SBRT, and IO, Ghassan?

PROF ABOU-ALFA: This is a very important point, and thank you so much, Dr Hassan, for that. If anything, historically the advent of use of radiation therapy to the liver was really not a — it was a no-no because we were worried about the liver. We don’t like fry livers with radiation. But with the advent of more advanced approaches in regard to radiation therapy now it is very safe and definitely can be very effective.

If anything here we should give credit, because that’s really who started all of that effort, is Dr Laura Dawson from Princess Margaret in Toronto. And I probably am humbled to say that when I was chair of the task force I really helped Laura to lead her study the NRG/RTOG-1112 that looked into the stereotactic body radiation therapy, or SBRT, that’s what SBRT stands for, stereotactic body radiation therapy, plus sorafenib versus sorafenib in patients with HCC.

And the study was presented, as many of us recall, at GI ASCO, and we were delighted in a way, and there was a little bit of concern about really the outcome per se that probably needs to be a little bit further tuned to really understand better if number 1, are these really the right combinations or should we think about something else. Interestingly, the advent of the checkpoint inhibitors come into play for regard to the SBRT plus checkpoint inhibitors, and this is something that definitely is of interest. I can say that here at Memorial we have a lot of lead effort in regard to that with Chris Crane and Carla Hajj, and we kind of like hope that we’ll see more of an outcome in that regard.

Now, can we have radiation with SBRT like yttrium-90 radioembolization? I would say that this is a little bit of 2 schools of thought between the radiation oncologist and the interventional radiologist colleagues in regard is SBRT and yttrium-90 to be compared. I think probably frankly the best I can really count on what we heard all the time from our colleague, Dr Riad Salem, who is really the expert in regard to radioembolization, they are different. And the radioembolization has a little bit of a more kind of broad perspective that really what Rich talked about it’s an affected liver to begin with. It’s really a precancerous component that the SBRT can’t really play a role quite a bit with.

However, to be fair we need randomized studies. These are not going to be any more like the old days. The way TACE, and the way the radioembolization, the way even the bad chemoembolization are approved based kind of the 5-10 approach, which is not a randomized study. I think randomized studies are critical because otherwise we’ll not be able to move forward with systemic therapy plus the local therapy.

DR LOVE: So when I heard that they somehow managed to get both of you on this webinar I was all excited because of course the big question out there in HCC is IMbrave150 versus HIMALAYA. You’re the PIs of both of those studies. I think 1 thing is great, that we have 2 really good options now, but I guess the question is which one in which situation. I’ll start with you, Rich. How are you looking at it?

DR FINN: Briefly, I think there’s some important differences between both studies to keep in mind. Very important is IMbrave150 took a very high-risk population, including patients who had main portal vein invasion. These are patients whose prognosis is very poor and are largely been excluded to many of the modern studies, the lenvatinib-based studies and durva/treme excluded these high-risk patients.

Despite having these high-risk patients IMbrave150 gave a significant improvement in overall survival. We know now that the hazard ratio is 0.59, and the survival for the entire population is over 19 months. There’s no study including high-risk patients like that that is globally done that has that data set. Also objective responses, 30%, very durable, and a safety profile that is really toxicity related to bevacizumab, that is hypertension, proteinuria, and bleeding events, which are generally low grade.

I would say that the first choice for me for a patient would be atezo/bev unless they have a contraindication. Contraindication to IO takes IO off the table regardless of the regimen. I think that’s uncommon.

Patients who are going to get bevacizumab for advanced liver cancer need an upper endoscopy within 3 months, and if they have high-risk features, varices that can’t be managed or recent bleeding, then atezo/bev won’t be a good option for them. But in reality I think that’s really 15% or less of liver cancer patients who are candidates for systemic treatment won’t qualify for atezo/bev, and there’s now real-world data from Dr Pinato’s group that reinforces this idea.

DR LOVE: So I was just flashing on the fact that actually we got both of you on a satellite CME meeting like 3 hours after Ghassan presented the HIMALAYA data. I guess that was ASCO GI February — about a year or so ago. So I heard similar thoughts from you at that point.

Ghassan, you also at that point verbalized a lot of interest in the HIMALAYA approach. Now that we have both options out there how are you deciding between the 2? Are you giving everybody HIMALAYA? Or what are you doing?

PROF ABOU-ALFA: So first of all, our colleagues in the audience, don’t worry, Rich and I are very close friends. You won’t believe how close we are. So that’s really just to make sure before. But here we’re defending points.

Number 1 is, and I recall very well when you asked me. This was in January 2021, and you asked me specifically who should give the durva/treme or the STRIDE or what the HIMALAYA study is about, and I said everybody, as simple as that. And this is my argument for that. Number 1, to be fair or Rich, there’s always what’s called first comer, and the first comer has an advantage, and by all means we all heard and learned about atezo/bev, exciting data, not to discredit it in any way. This is incredible. For the first time, we were talking about like median survival 3 months, and now we’re talking about like 19 months. This is like unheard of. So this was a big deal.

On the other hand, interesting enough, that when it came out the number became kind of clinked into all of our minds, 19, 19, 19. Interestingly enough you can really walk on the stage at ASCO — GI ASCO, and people on the stage say, if you say HCC, they’ll say atezo/bev. That’s...and to be fair there’s nothing wrong with that.

However, to be fair, as I always say, with every study that we have a positive answer it brings with it many questions. And the first is already what Rich mentioned, and please this is more of a statement rather than anything else, and really the second thing with Dr Finn said here, please, please if you decide, and you’re insistent to do atezo/bev, make sure you scope the patients. It’s very sad, and unfortunately it’s appalling and really upsetting to see that patients have bled because they were not scoped after giving bevacizumab. And as we know from the study that was done by our colleague Abby Siegel a long time ago with bevacizumab on its own, people died. So there’s no question that endoscopy is critical, as we just heard from Rich.

The second point, though, that I would like to bring, which is referring to the population we’re dealing with. Because always when a person tells me the median survival is X, I say who are the patients, because demographics of the study will matter quite a bit. And one thing that we can look at, and this is the data that we have, that in the atezo/bev 50% of the study was actually hepatitis B.

On the other hand, in the HIMALAYA 30% were hepatitis B. The HIMALAYA was generally way broader in regard to global presence, while the atezo/bev and the IMbrave150 was with more of Asia present.

Interestingly, then here we go, we hear from our colleague Pinato, and Rich just mentioned him, with his very bright young colleague, her name is Dr Fulgenzi, they bring it in and say we did the real-world data on atezo/bev, what’s called the AB-REAL study, and the median survival was 15.7 months. Woah. Where’s the 19? Where did it go? Interestingly, less hep B, more hep C, more NASH. And we know very well nowadays, this is by the way across the board for all the studies, the hep B will always fare better than the hep C, that will always fare better than the nonviral in regard to any checkpoint inhibitor. It does not mean we don’t give it for the nonviral. We give it to everybody, but the expectation is that the patient with hep B will probably fare the best.

As such, if you redo the HIMALAYA in let’s say only hep B, you’re going to get a higher number. And we saw that number, by the way, not that long ago in regard to the study that was presented at ASCO — sorry, at ESMO, which was looking into camrelizumab plus rivoceranib, another combination of anti-PD-L1 plus anti-VEGF, and guess what the median survival was, 22.1 months. And guess what? The study 100% done in China. So what do the patients have? Hep B. So that’s important to really look at the specific demographic of patients. That will give you a reading in regard to that.

The last point I would like to bring up in regard to the atezo/bev. To be fair, this is an important point. We don’t know yet what’s important, and probably I’m softening a little bit about that because I’m not really seeing yet what it implies in regard to the final outcome. But it’s really kind of like a little bit concerning that the FDA itself brought up the issue of the antidrug antibody — and they said 30% of the patients, which by the way I give credit to Rich and his team. Actually what they reported at the AACR were 30% of the patients will have an antibody against atezolizumab. And interestingly, the hazard ratio will turn from the efficient 0.5 or so all the way to 0.97, equal to sorafenib. While interestingly durvalumab has only 1.5% of antidrug antibody potential.

So I think there are some issues in regard to atezo/bev that time will tell more of. But if you ask me like my final answer I think atezo/bev, durva/treme, or also this new combination that we heard about, camrelizumab plus rivoceranib, I think probably they’re all equal after all.

DR LOVE: So again, we could talk about this a long time. But just one other point I’m curious about, Rich, and you can see that Ghassan talked about a couple of papers looking at IO plus TKI, so not bev, but VEGF through TKI, one with cabozantinib, another the lenvatinib/pembro LEAP approach. And it kind of didn’t seem like you saw, I mean again, it’s hard to do cross-trial comparison, as much efficacy with TKIs. Also, the lenvatinib arm was really great outcomes in the LEAP study. Any thoughts about that, Rich?

DR FINN: Ghassan and I are very good friends, and we are 2 of the people who really have had an interest in liver cancer for 20 years and have seen it evolve. And just real quick, Ghassan, looking at IMbrave150, actually the hepatitis C patients actually did the best in that study, with a survival of 25 months, so I don’t know how important etiology is. But it’s also very relevant when we start looking at the new combinations.

The LEAP-002 study looked very promising based on early data that lenvatinib and pembrolizumab had some synergy, and in reality the Phase III study recapitulated the single-arm data very well. We had a survival of 22 months with len and pembro, a very high response rate. And this just goes to the point of how the natural history of liver cancer has changed. The control arm of lenvatinib in a double-blind placebo-controlled study — keep in mind most of the IO studies are open label, IO versus a TKI. But this study had a TKI in both arms, and the lenvatinib had a survival of 19 months, really impressive, showing the change in the natural history of HCC. But again, this study did not include patients with main portal vein, so that 19 months is not the same population as we saw with IMbrave150.

Cabozantinib and atezolizumab was also building on this idea that TKIs can modify the immune microenvironment, hitting unique kinases, and we know cabo is active in liver cancer. But while this study did meet its PFS endpoint, you see that here on the top, it did not meet an overall survival endpoint, a secondary endpoint. And also somewhat puzzling is the objective response rate with this combo was only 11%, less than what we see with single-agent IO. And taken together this regimen really did not move forward for FDA approval.

DR LOVE: So before Ghassan starts, because I know he could go all day long, and I swore we were going to get through HCC halfway through, but we’re not going to make it, but anyhow, Ghassan, one more point, and then we’ll get to biliary tract. You also were talking about cabozantinib, and there were a couple papers that came out of the CELESTIAL trial, second line after sorafenib. One was the efficacy in patients with Child-Pugh B liver function and another paper looking at quality of life. Can you comment on those papers, Ghassan, and also your clinical experience with these issues with cabozantinib?

PROF ABOU-ALFA: Sure, by all means. So Neil, again, thanks for bringing up the cabozantinib, just with respect, many of us do remember before the advent of any checkpoint inhibitors all of us were excited about the cMET inhibition. And there were many cMET inhibitors, among which cabozantinib. And — tyrosine kinase inhibitor it can address other things, like AXL, VEGF, et cetera.

And I recall, like if you asked like what did I contribute to the study that we are very proud of and we published in The New England Journal of Medicine, interestingly I supported this sponsor on, as I said, bring it to everybody. Don’t really choose the patients based on their cMET expression, just treat everybody, because we don’t know how much the role of the anti-VEGF, anti-AXL, anti-cMET, et cetera; treat everybody. And we were very proud the study came out positive and really it’s a drug that’s available not only in second line but also in the third line, in fact the only drug that’s available in third line in HCC.

Now no doubt that our experience, and our colleagues in — the community physicians, which I totally agree with you, Neil, they are way ahead of us in understanding, and they have experience in regard to other diseases as well. They are not a big fan of cabozantinib because of adverse events in regard to other cancers, and as such there’s a bit of hesitance in regard to the therapy, but I would say that the 60 mg adjustment to 40 and possibly 20 is definitely less likely to happen.

But interestingly we tried to even dissect that further, and I give credit to our dear colleague, Dr Anthony El-Khoueiry, who actually led on that effort, that part of the cabozantinib study, that looked into the patients who really have a Child-Pugh B scoring which has been worsening. And no doubt that we can see that despite that we can see that clearly still the patients will actually still benefit from the cabozantinib.

Now this is — I will take it with a little bit of a grain of salt, even though I was a senior author on it, but to be fair this is really a population that the B7 is another story compared to B9. So we have to be very careful and thoughtful about really what does it mean in that regard per se.

The second part that you brought in is the quality of life. And no question that the quality of life component is really important, and yes, despite that some of the hesitancy in regard to the cabozantinib, as I just mentioned, I would say still at the end of the day patients can do well with it. So is it a worthy drug? By all means it is.

Biliary Tract Cancers

DR LOVE: All right. Well let’s talk a little bit about biliary tract cancers, and I think I was sharing with you, Rich, that I like to call biliary tree cancers the new non-small cell lung cancer because there’s so many targetable lesions there. But one of the things you got into in the beginning of your talk, Rich, that maybe you can just summarize a little bit, is an overview of this disease, correlation between anatomy and biology, and what we’re seeing in terms of potential targeted lesions?

DR FINN: Yeah. For a relatively rare malignancy we are seeing more of it, and we are making some great strides in managing it, but there’s still a lot of work to be done.

Anatomically, we break these into intrahepatic, tumor arising within the liver, the intrahepatic ducts, then we talk about tumors that occur at the hilum, the so-called Klatskin-type tumors, and then there’s the extrahepatic bile duct, which goes from the liver to the ampulla. And then there is also the gallbladder and gallbladder cancers.

What do they share in common? Well, that biliary epithelium can be exposed to various insults that can give rise to tumors, and there’s been excellent, excellent profiling work on these tumors, which has increased our understanding of the biology of this disease. And while there are actionable mutations they tend to track with tumor location, which is a very interesting observation.

And now that we have the molecular understanding of the disease, FGFR2 alterations, genomic translocations, there are now FDA approved agents for that alteration. Ghassan played a pivotal role in the approval of IDH inhibitors, ivosidenib, and more recently we’re seeing IO come to the front line. HER2 amplification has been around a long time but occurs more frequently in some of the gallbladder cancers, which is a relatively rare subtype, and then a rare alteration. So there’s challenges in developing high-level evidence for this disease, and certainly biomarker-driven studies have been challenging to accrue to but really take a great effort.

DR LOVE: All right. Well we actually have a couple things in the chat room that are kind of interesting. So Ghassan, Emily has a patient with IDH2-mutated cholangio. What do you recommend second line after chemo/IO? Hold off on the answer to that one. Just keep it in your mind. And now Dr Kumar is back with another patient. He has a great practice. So he’s got a patient with a 5.0 x 4.0 x 3.5 cm tumor resected that was read as a combined HCC and cholangio, and he says is the prognosis determined by cholangio? Should I give chemo and durva based on TOPAZ and forget the HCC for now, or treat the HCC?

So those are a couple cases we can keep in mind, but first let’s get to the first-line situation because this has changed recently, as we talked about. So first, of course, we saw the TOPAZ study looking at durva plus chemo, gem/cis, which saw a benefit. So that was great to have that option. I’ve heard a lot of cases being presented to me of people getting treated that way. But then we just had another study, very similar, to me it looks very similar, Katie Kelley presented it at AACR, I think, and then published immediately in Lancet, pembro with gem and cis. Kind of looks similar, to me, like hazard rate about 0.8, 0.82.

Ghassan, what’s your take? Is this like going to be a coinflip or — and are you using this strategy? I mean it’s not the most amazing outcome, but it is positive.

PROF ABOU-ALFA: No. By all means, what impressive work, and very delighted to see it as well. There is actually one little caveat of difference between the 2 studies, which probably kind of like probably play a role. Interestingly, in the first one, in regard to the durvalumab, the TOPAZ, the gem/cis was stopped exactly at 6 months, same like the ABC-02 study.

And by the way, for our colleagues in the community, this is not really something that we like to decide, but interestingly in the UK, as you know, there is like a system where they really kind of like rank and kind of like value quality of life and life, and this is something that we don’t talk about here in the US. And as such they decide how much therapy you can give for patients, how much contribution can this do. And there was a decision in the ABC-02 study of gem/cis just stop at 6 months regardless of what the patient’s outcome is. So the TOPAZ led to — or was obligated to compare to the ABC-02 study, so 6 months of gem/cis only, and then after that carry on with the durvalumab.

In the new study, the KEYNOTE-966, interestingly after the 6 months actually the gemcitabine is carried on with the pembrolizumab. That’s quite fascinating. And if anything it really brings in the question is this really what should happen afterwards.

I’ll talk about life — clinical experience. We have noticed that proudly, by the way, with gem/cis/durva, have we seen CRs? Yes, we did. Actually already I’ve showed it 3 times. But have we seen recurrence at some point after a CR? Yes, we have seen that as well. And interesting what we have done is to really retrigger with the chemotherapy, and as such an approach with similar or a little bit more, the KEYNOTE-966, i.e. you drop the cisplatin at 6 months, keep the gem, and continue the durva, probably is a good idea after all, because remember, it’s a cold tumor. It needs to be heated up by certain chemotherapy, and that’s where the gem can play a role.

But other than that, you are absolutely right, Neil, they are equal. It wouldn’t matter, as long as you’re giving chemotherapy plus some form of checkpoint inhibitors you’ll be okay, and you’ll treat patients correctly.

DR LOVE: So Rich, what are your thoughts? And any thoughts about this case Dr Kumar has? I heard about this combined thing where you can’t tell which one it is. How do you approach a case like this, Rich?

DR FINN: Yeah. So I agree with everything Ghassan said. In clinical practice I have a lot more experience with TOPAZ. In research we were the lead US accruer in KEYNOTE-966, and so I have some experience with patients in that regard. And it certainly is the standard of care to introduce IO front line. Personally, I continue chemo. If it’s not broken why fix it, right? If patients are doing well, they’re tolerating it, they’re having benefit, I tend to continue.

Dr Kumar has identified a real entity. We know that this mixed cholangio/hepatocellular pathology does exist. Likely there is a common cell of origin that has a mixed differentiation, and this tends to be a worse prognosis than a pure HCC. In fact, so much so that mixed cholangio/hepatocellular carcinomas cannot be eligible for transplant.

In this setting I would probably offer this patient capecitabine adjuvantly in the context of the BILCAP study to try to prevent the recurrence of this cholangio component. It’d be interesting to know why this patient developed this tumor. Do they have PSC? Do they have hepatitis C? but clearly there’s an abnormal biliary epithelium here, and I would offer them cape.

DR LOVE: Okay. So Ghassan, the chat room’s blowing up with great cases. Michelle: Patient with deficient MMR, cholangio, I love how this one starts, high TMB, Stage IV, progressed on gem/cis/durva. Would you give more immunotherapy second line like ipi/nivo or something? MMR deficient.

PROF ABOU-ALFA: That’s a beautiful example. That’s a beautiful, beautiful question. Interestingly enough, the approach that we are taking in clinic, even though we are used to the idea that you just have progression of disease, you consider all therapies that you’re giving are really not working, and you change to something other therapy, which is exactly what the question is.

Interestingly, the way you can approach the checkpoint inhibitors, and there’s like some biologic argument for that, it’s a scaffold of a building. And if anything what you add on as chemotherapy, being like the gem/cis or what have we, it’s like just slapping walls onto the scaffold of the building. And as such, if there’s a progression you can very much argue to keep the scaffold the same way, ie, keep the checkpoint inhibitor, ie the durvalumab, and take off the walls and put new walls on with the new therapy.

And we have done that before, and for example moving on from the gem/cis plus durvalumab to liposomal irinotecan/5-fluorouracil plus durvalumab, even followed after that the FOLFOX/durvalumab is not like an unheard-of component. And I would recommend personally, at least by experience, even though we need proof for that, to keep the checkpoint inhibitors while continuing to change the therapy.

DR LOVE: I love those analogy type things, the scaffolding, all that. I just flashed on at ONS. I don’t know if you know Rich Stone from Dana-Farber, he made the analogy between MDS and a factory where all the workers are drunk, the marrow is like a factory where all the workers are drunk.

Anyhow —

PROF ABOU-ALFA: I should ask about what CTLA4/CD28 story they have.

DR LOVE: All right. FGFR inhibitors. Actually, we talked about this in our bladder program in AUA, Rich, also. You have erdafitinib approved, the big issue there. But here we have different FGFR inhibitors, and you went through that in your talk. Can you kind of provide an overview of these alterations, how often you see it, and where we are right now with FGFR inhibitors?

DR FINN: Yeah. It’s a very exciting story because so long we were always focused on mutation, right, and that was the rationale for a lot of kinase inhibitors taking from the — taking from the lung cancer experience so to speak. But in the early studies with these inhibitors it turned out that it was not point mutations but genomic alterations, where FGFR2 gene is typically translocated to another partner. And these translocations tend to occur within a certain frequency in intrahepatic cholangiocarcinomas more frequently.

And it looks like — my typical patient is a younger woman who has no underlying liver disease who presents with these alterations. And now these drugs have been shown to have significant response rates, 35-40%, in this population, higher than chemotherapy I would state, and are an important option. The challenge is like we see with many kinase inhibitors, patients eventually develop resistance, and we’re still trying to sort out the role of newer FGFR2 inhibitors to see if we can overcome resistance to the first generation, so to speak.

But this story highlights the importance of doing molecular profiling, and for that patient we just heard about I largely do agree with Ghassan. I often try to keep IO ongoing if I’m combining it with chemo; insurance companies approval required. But that patient should have molecular profiling because perhaps they do have one of these actionable mutations such as FGFR2 translocations.

DR LOVE: So Ghassan, I’m kind of curious. Again, in lung cancer when you see targeted therapy that has a response rate that’s getting up to 50% or more they just start using it first line. They don’t do randomized studies anymore. They just give it first line. Any situations, older patient you don’t want to give chemo to, et cetera, where you might want to use targeted therapy first? Like FGFR inhibitors?

PROF ABOU-ALFA: By all means. You bring up a very important point, Neil, and to be fair, I think our colleagues in lung have done way better than us. But to be fair, not for any reason but it’s way easier to get a biopsy in the lung. It’s less complex in regard to the complexity of the biliary tree and the bilirubin elevation and what have we.

Regardless of this, I totally agree with Rich, very critical, I mean my oldest joke is if the patient coming to Memorial Sloan Kettering in the middle of Manhattan they should be getting their next-generation sequencing while walking in, like this is really how early it should be done, because this is very critical information they need later on in time.

Now, the approach that we’ve been looking at is randomized study, you compare this to a standard of care. You compare an anti-FGFR2 to the chemotherapy standard of care, and you find out what’s going on. In reality, we all got excited, but in reality the FGFR fusion happening in real world is about 5%. And as such, a really rare cancer to begin with, now you have only 5% of patients with that genetic alteration, and you’re going to do randomized trial? Already we tried. It did not work. Actually already the infigratinib is already pulled out even altogether. The company is not even pursuing it any further because it was likely…failure.

And this is where our obligation is to really have a sit in with the agency that maybe for those alterations we don’t need randomized Phase III clinical trials. And at the same time, could we treat patients with this approach? Yes, we can.

One, I’ll give a good example of that is the BRAF V600E, which can happen in biliary cancer. And this is nice work that I give a lot of credit for Dr Subbiah and Dr Javle from MD Anderson, beautiful work. And if anything I was casually interviewed on at ESMO, and they said would you give it first line, I said absolutely. There is no question about it that this is really a great response, by all means we should definitely apply it when we can.

The problem is we don’t have that data for the other genetic alterations, and that’s why maybe a new approach in regard to the approval of those studies should be looked into rather than through the classic Phase III clinical trials that we have been doing since 1960.

DR LOVE: Well, as you say, they’ve got the precedent for sure because that’s what’s happening in lung.

Rich, what about — what do we know about the currently available agents? What’s the difference between them? And maybe you can comment a little bit on efficacy, but also tolerability because this is a different class of agents with some interesting side effects. First, can you talk a little bit about what we know about pemigatinib?

DR FINN: Yeah. So pemigatinib is one of the first-generation FGFR-TKIs. It hits several of the FGFR family members. It was one of the first to be approved. It’s dosed 2 weeks on and 1 week off, and it is irreversible, right? And we know some kinase inhibitors are reversible, some are irreversible, depending on their mechanism of engagement with the target. But needless to say, for these fusion patients, these translocated patients, the objective response rate was like 37%, with a — very durable for a kinase inhibitor, around 9 months, and survival in a single-arm cohort study was over 17 months. And this was second line.

Now FGFR has on-target effects. FGFRs, these receptors are very important for regulating phosphate metabolism in the kidney, and therefore hyperphosphatemia has to be watched for. These patients can develop hyperphosphatemia, and these patients need to be treated for that with a phos binder, sometimes being recommended to be on a low-phos diet, but very generally very manageable with those interventions.

But then we have these unpredictable side effects, which when we give patients chemotherapy we can say you’re going to have alopecia, you’re going to get nauseous, you’re going to have cytopenias. But the kinase inhibitors can be somewhat unpredictable, and with these drugs often we can see still alopecia, GI toxicity, and often a very uncomfortable dermatologic finding of these changes in the nails and the nailbeds that can be very problematic for patients and affect their quality of life. I’ve had patients who’ve actually lost their nails from this inflammatory reaction.

Now there’s a new FGFR inhibitor that was approved only in the past few weeks, earlier this year, and Lipika Goyal from Mass General, now at Stanford, had led this study of futibatinib. And unlike the other FGFR inhibitors that preceded it, this one is irreversible, and it’s dosed continuously. And in this study of FGFR2 fusion arranged patients the objective response rate was just about 42%, in range of what we saw with pemigatinib, with a long duration of response and a very mature survival.

Now this drug, as they presented in the publication, does have a little different kinase profile. It hits some of the alterations that pemigatinib does not, some of the potential resistance mechanisms, but I think we’re not in the state that we necessarily save this drug for later. I think at this point for a patient who’s progressing on front-line treatment we now have currently approved 2 FGFR inhibitors for broad use, pemigatinib and futibatinib. And again, the side effect profile seems very similar to the other compound.

DR LOVE: So Ghassan, actually the nurses at ONS — we were talking a lot of about these FGFRs and what they do with the nails and all that. But this is a new arena for, I think in oncology, some of these, particularly hyperphosphatemia. Anything you want to say about your own clinical experience with these agents, and any clinical pearls about how to utilize them, Ghassan?

PROF ABOU-ALFA: Sure. By all means. I first concur, and I 100% agree on all that Rich said in regard to the potential adverse events. And I will start by saying that the first step is to make sure that a patient should get a retinal exam. Because if ophthalmology retinal exam is critical to have as baseline. It’s not going to be a decision maker one way or the other, but the potential for having or building subretinal fluid foci, which are typical of MAP kinase inhibitors as well, could be a potential adverse event. So you need a baseline to really compare to in case the patient comes to you with a little bit of a halo of unclarity or darkening one side of the hearing — sorry, of the vision.

Number 2 is you have the phosphate, and number 3 of course you have the skin are of course the other 2 adverse events that could occur.

Interestingly, what we learned over time, and we have been really heavily involved in regard to the infigratinib and pemigatinib now, we really are more saying that maybe we’re sometimes overreacting. We should be very careful how much we’re going to treat things. Ironically, and probably this is like a little bit kind of a sobering fact, one of the side effects of the first study that reported in infigratinib was actually hypophosphatemia. We actually treated patients way enough to make them hypophosphatemic rather than they were hyperphosphatemic. So we have to be very careful how much we treat things, and it’s not treating numbers, it’s treating patients. It’s very important to follow what Dr Finn just mentioned, but we have to really put all measures within the context of what’s going on for the patient.

All in all, I think the experience is teaching us better. Yes, the finger and the fingernails can have the problem. If anything, it’s something to be aware and conscious of as well. We proudly have at Sloan Kettering, because we are really multidisciplinary in every approach, we proudly already published with our colleagues in ophthalmology, Dr Jasmine Francis, on the retinal alterations. And fascinating is that this is reversible. You stop the drug, it can recur, and it can improve, and then you can restart the drug again.

Number 2, we’re working with Mario Lacouture in regard to the skin toxicity, and this is something that’s evolving in a dynamic way to really get some very detailed guidelines that will help people and at the same time make it practical for them to use the drug.

All in all, good drugs, definitely not to be missed, and at the same time to really be cautious of the adverse events.

One word if you’ll allow me in regard to the differences between the 2 drugs, or the many drugs that we have. There are a couple of schools of thought that are happening as we speak. On one hand I’m really fascinated by the work that actually Dr Goyal has brought in regard to futibatinib, and add to the irreversibility there’s the multitargeting, which is FGFR1, 2, 3, and 4. And you say like you know what, like going to war. The more weapons you have the better it is, but interestingly do we need that kind of diversity or do we need more specificity.

Because the Relay drug, which is not yet approved for that indication, or any indication, interestingly enough is highly specific for FGFR2. Do you want really a spread out weapons, or do you want like very highly targeted weapons? This is something to really think about a little bit more as we produce more productivity in that regard. And I give credit here for my colleagues James Harding and also Alison Schram, or Al Schram, that work on the Relay, quite interesting to see a highly specific and with — which is incredibly, incredibly efficient, is causing an improvement in regard to patients with intrahepatic cholangiocarcinoma.

DR LOVE: So a couple of final points. So Rich, you covered a couple of anti-HER therapies in biliary tract cancer. Of course, you’ve done lots of work with Dr. Slamon over the years in trastuzumab in HER2-positive breast cancer. We actually at ONS did a meeting where we talked about HER2 in breast cancer, GI, and lung in the same conference. We had your colleague Zev Wainberg there incidentally.

So I don’t know if we get an hour looking at biliary tract, and you can see T-DXd, which is what we were talking about mostly at ONS, looks like does cause responses, as it seems to in many other. I think in endometrial they’ve seen it as well, but also this bispecific, the nickname is zani, it already has a nickname, zanidatamab, a bispecific that — it’s not an immune bispecific, it’s like a targeted bispecific.

So Rich, you covered these in your talk extensively, but any thoughts about anti-HER therapy? How often do you see “HER2-positive”, even HER2-low, and any thoughts about whether this is going to play out in the future?

DR FINN: Yeah. I mean we are generally looking for genetic alterations in HER2 in bile duct cancers, so this idea of HER2 high and low, which has taken over the breast field, I don’t think has come to play yet in biliary tract cancers. We’re still looking to get a HER2 therapeutic FDA approved. Even though some have NCCN listing, FDA approval is what’s really required to help push these things forward.

Zanidatamab is a HER2 antibody that hits 2 different epitopes on HER2, kind of like using trastuzumab and pertuzumab together, and is showing very encouraging response rates. Again, 41% in a single-arm study, and these are patients who are amplified or high by immunohistochemistry. And really there’s no new safety signals in using this compound against HER2, a very clean side effect profile.

And that goes to be said for trastuzumab deruxtecan, and antibody-drug conjugate that’s really changed the way we treat HER2-positive cancers, breast and gastric potentially. And again, in patients who are HER2 amplified 36% response rate. They did look at this HER2 low, and there was some responses but really I think moving forward with this compound for registration would be to concentrate on this HER2-amplified cohort.

The challenge is it’s relatively rare, in mostly gallbladder cancers, and so hopefully we can maybe just expand the cohorts. Instead of having 20 patients maybe a large, 100-patient cohort or more would be a strategy to get approval, as has been done with the FGFR2 inhibitors. But I think HER2-directed therapies are taking way too long to get to this indication. It’s been known about for a long time, but biliary tract tumors are often an afterthought. I used to say that about liver cancer, HCC, but even more so with biliary tract tumors. But they’re coming to primetime now. It’s recognized that there’s a large unmet need.

DR LOVE: And in terms of zani in HER2-positive breast cancer, which I’m sure the whole audience is thinking about, they have done a Phase I study of zani monotherapy in breast, and they did see responses, a number of them. I think there were 20 patients, maybe 36% response rate.

A final comment. Another thing you covered in your talk, Rich, was seribantumab, the CRESTONE study looking at NRG fusions. Talking about uncommon, extremely uncommon, but you see efficacy there. Unfortunately I guess the drug, though, has been put on hold in terms of development for, I don’t know, financial not medical reasons, or research reasons. It is an exciting agent. So hopefully they’ll be able to figure out a way to keep studying it.

But Rich, what’s the bottom line in terms of this is very uncommon, difficult to do studies when they’re so uncommon. It looks like it’s pretty effective targeted therapy. Any comments, Rich?

DR FINN: Yeah. I mean the cholangio cohort in this study was very small. They didn’t report a lot of activity there specifically, but in the lung cancer group this was an active drug. And what’s interesting is when you have these neuregulin fusions HER3 is a very important target for them, and this antibody is against HER3, a first in class so to speak, but we’ll have to wait to see more on that story.

DR LOVE: So Rich and Ghassan, thank you so much for joining us tonight. Audience, thank you for attending. Come on back on May 17th, have a couple cups of coffee before we start talking with Joyce O’Shaughnessy because it’s going to go fast but be a lot of fun on May 17th. Be safe, stay well, and have a great night. Thanks so much, Ghassan.

DR FINN: Thank you very much.

DR LOVE: Thanks so much, Rich.

PROF ABOU-ALFA: Thanks for having us. Thank you. Thank you, Neil. Thank you, everybody.