Redefining HCC Treatment in the Immunotherapy Era: Expert Insights, Multimodal Innovations, and Coordinated Care for Optimal Outcomes Across the Disease Continuum

And I'll be talking to you first today about immunotherapy in advanced and metastatic HCC.

[00:34:14]

BCLC Staging and Treatment Strategy for HCC

So when we talk about HCC treatment, we typically use the Barcelona Clinic Liver Cancer Staging System. What's interesting about this staging system is it incorporates not just tumor burden as most staging systems do, but also the degree of liver dysfunction. So as we move from early stage to advanced stage disease, in addition to increasing tumor growth at the primary site and perhaps spread to additional sites, there's also a feature of advancing liver dysfunction, which can play a significant role in management options and disease course.

So in the advanced stage setting or BCLC stage C, this signifies that the tumor has extrahepatic spread or portal vein tumor invasion. Usually when we discuss therapeutic options, this is in the setting of well-preserved liver function. So Child-Pugh A cirrhosis and relatively good ECOG performance status.

So as you - as you can see in the BCLC kind of schema, typically the mainstay of therapy in advanced stage disease is systemic therapy.

[00:35:26]

FDA-Approved First-line Systemic Therapy Options

So we now have 3 FDA approved front-line systemic therapy options in advanced stage HCC. These were approved on the basis of the results of 3 front-line randomized controlled trials, phase III trials, which we summarize here.

First, the IMbrave150 trial evaluated atezolizumab plus bevacizumab vs sorafenib in this patient population. And the investigators found an improvement in median PFS, median OS, response rate, duration of response, significance. So that led to the approval of atezolizumab and bevacizumab in this setting back in 2020.

Next we have the HIMALAYA study, which is a very large, randomized phase III trial evaluating a priming dose of tremelimumab in combination with durvalumab, the so-called STRIDE regimen, also vs sorafenib, because that was the standard of care when this trial was enrolling. And in this study, we found that the median PFS was actually not different between the 2 arms of the trial, but the median OS and the response rate and the durability of responses were improved with the combination immune therapy regimen vs the control arm.

And most recently, we've seen the CheckMate 90W study, which evaluated nivolumab and ipilimumab vs investigator's choice of lenvatinib or sorafenib for patients with unresectable HCC. In this study, again, we see no difference in the median PFS, but an improved median overall survival and response rate and duration of response.

So I think it would be a nice point here to pause and to discuss with my colleagues here their thoughts on these 3 regimens and how they perhaps think about how to select which regimen to choose for their patients.

So Dr Yarchoan, what do you think about these data or anything else in this space?

Dr Yarchoan: Well, this is a great problem that we have in our field, right? I mean, when I came out of fellowship, we had 1 drug, sorafenib, prolonged life by 2 to 3 months and was pretty miserable for patients. And now we have this menu of options. And, you know, I think sequencing becomes a real challenge now, also, when we have all these drugs.

You know, I think 1 thing that's pretty clear, even though we have no head to head data is that the duration of response with CTLA-4 based regimens really does seem to be quite impressive. And so if you respond to immunotherapy, you respond for a long time, particularly with CTLA-4–based regimens.

And I think if you look at both the HIMALAYA data and the CheckMate 90W data, the tail end of the curve is really quite impressive. You know, I think IMbrave150, you know—it was the first approved and in many people's practices has remained a sort of standard frontline option for patients. It's well tolerated. It's the only regimen that really has prolonged not just overall survival but also progression-free survival.

And I think that that is really driven by the bev. So it protects the front part of the curve, which is very nice. And I think we've all become very accustomed to dealing with bev. So, you know, there are certain patients who shouldn't get certain regimens, but there are patients who are candidates for all 3 of these regimens, and unfortunately, without head to head data, it's very hard to decide what to do.

Dr Franses: Absolutely. One thing I didn't mention about these 3 regimens is the last row of this table. So each trial measured toxicities; we’ll go over some of the details, especially in the 90W study. But there is a significant difference across these regimens in immune-related adverse events which require steroid management.

And so maybe Dr Parikh, would you like to comment about how that may influence your decision making?

Dr Neehar Parikh (University of Chicago): Yeah. I think that we think about toxicity a lot when we think about any kind of systemic regimens. And, you know, on the one hand, there's the bev-related toxicities that we worry about and, you know, the need for an upper endoscopy for patients, you know, getting bevacizumab because of the risk of GI bleeding that's associated with it, and was 1 of the inclusion criteria of the trial.

On the other hand, you know, the immune-related toxicities can be higher when you add a CTLA-4 plus the PD-1 inhibitors. So I think it's a kind of a balance between those 2 things. So I think in a patient that is robust maybe not a lot of portal hypertension. I think the atezo-bev as, Mark mentioned, is a lot for a lot of people, a frontline therapy. For patients that may be more intermediate, maybe the HIMALAYA trial shows that those patients can get STRIDE regimen in a safe way.

And then, I think we still have emerging data on nivo-ipi. It's kind of new. And I think people are really trying to figure out this, but I think the toxicity in that regimen is real. And we've seen that in both the second-line and the first-line study. And we'll talk about that more.

Dr Yarchoan: I mean, you know, I think as patients live longer and longer and we have more drugs, we also have to think about sequencing. And, you know, at the end of the day, most of my patients are - are receiving multiple lines of therapy, 1 of which includes an anti-VEGF agent and 1 of which includes an anti CTLA-4 agent.

I wish that we had data not just of these agents in isolation, but also just how patients did with various orders of therapy. You know, I'm using already, even before the ipi-nivo frontline approval, it was something that I would reach for in subsequent lines after bev-atezo and I saw some great responses, even in second and third line. So it's clearly an active regimen. There are responders to CTLA-4 who don't respond to atezo.

So, you know, I think we have to think about all these drugs on a menu in various lines of therapy.

Dr Franses: All right. Great points.

[00:41:28]

BCLC Staging and Treatment Strategy for Advanced HCC

All right. So now we're moving on again to the BCLC staging system in a little bit more detail. So zooming in a little bit, with the recent approval of ipilimumab and nivolumab, we have again 3 frontline FDA approved options for patients with BCLC Stage C HCC.

As Dr Yarchoan mentioned in the second-line setting, now it’s quite difficult to point to hard data to guide our decision-making in that setting. And so certainly after front-line dual or combination therapy, the subsequent options depend on what agent you got before, you know, perhaps what toxicities emerged from those. So it's actually a relatively complicated and data light zone I would say.

Dr Yarchoan: Yeah, I think, you know, just to comment quickly, I think if patients get a dual IO agent and front-line, you know, just based on first principles, I would give them a TKI in second-line. They've never seen an anti-VEGF agent. You know, we know that lenvatinib is—or sorafenib or active lenvatinib prolonging PFS more than sorafenib, probably.

You know, after atezo-bev, I think, you know, a TKI still remains the default second line, but I think there is a role for consideration of IO-IO also. But regardless, you know, there - I would say clearly patients should be getting dual immunotherapy based regimens and frontline, unless there's a clear contraindication.

Dr Franses: I think you published some data for ipi-nivo after atezo-bev that you alluded to, whereas the front-line response rate was around 36% in CheckMate. from your data set, I think it was more like 20%. Is that correct?

Dr Yarchoan: Yeah. And there have been other data sets as well. So it clearly has activity and is something we should keep in our toolbox.

Dr Parikh: How they respond to atezo-bev, if you do use that in frontline influence what regimen you might choose in the second line?

Dr Yarchoan: Yeah. I mean, it's such small numbers of patients in these retrospective studies. I would have anticipated the patients that responded to atezo-bev would have been the ones to subsequently respond to ipi-nivo. In our very, very small analysis, actually it was the exact opposite. It was the patients who had primary progression on atezo-bev, who seemed to actually respond to ipi-nivo. You know, maybe they just need that CTLA-4 priming. But small numbers of patients. So it's hard to know.

Dr Franses: Yeah, I think that points to the need for predictive biomarkers in this - in this and really all settings, you know, for immune therapies. You know the standard biomarkers that have shown some utility in other settings really haven't helped us much here.

[00:44:24]

IMbrave150: Bleeding Events

All right. So moving on to the safety profile of immune therapy regimens in advanced stage HCC. So just reviewing briefly the bleeding events in the IMbrave150 data. Again, this is the concern about the bevacizumab component.

We can recall that in terms of the significant, meaning, grade 3 or higher bleeding events is around 3% in terms of GI hemorrhages or esophageal variceal bleeds. Actually not so different than sorafenib vs also an antiangiogenic drug. And really the time to onset was actually somewhat prolonged and similar between the arms atezo-bev and sorafenib around 6 months to any toxicity related to bleeding. And then similar to the severe toxicities.

Dr Yarchoan: Maybe we can talk about that for a second.

Dr Franses: Yeah, sure. I mean we have an expert hepatologist here. So, you know, I think when atezo-bev was first approved, we all read the FDA label. Yeah. Got everybody in endoscopy before we dared to give them a dose of bevacizumab. And, you know, I can remember patients who, unfortunately, had massive, rapid progression in that time that we were trying to negotiate getting an EGD[?].

You know, looking at this data, it takes 6 months before you have a bleeding event, you know. Were we too conservative, do you think?

Dr Parikh: Yeah. It’s a little bit difficult because the inclusion criteria, right, were that the patients had to have an EGD, had to have some sort of management of that. You know, there was a little bit unclear from the data exactly how that was done in the enrollment. But there was a selection bias here to start. And so that's part of the reason that this recommendation has continued.

Now, if a patient is a noncirrhotic patient with advanced HCC, do you need to get the upper endoscopy, no portal hypertension on imaging? That remains unclear. And actually how exactly you manage the varices, again completely unclear. But you know, our group has worked on these noninvasive ways to try to figure out if somebody's got high risk varices and developing these algorithms. But as of right now, just given the inclusion criteria, I think, you know, if somebody has evidence of some portal hypertension, probably should get an EGD just given the way that we've done that.

Now, most of the bad bleeding events for varices were patients with main portal vein invasion. So I think that's the other part is, you know, probably those are the highest risk patients. They have portal hypertension out of proportion to what you might see on imaging. So, definitely have to get an EGD and those patients with more advanced vascular invasion. But it's hard to say anything differently just given the selection bias in the study.

Dr Franses: Yeah. I also would add that in the patients who have a bevacizumab-related toxicity, that's reversed, you know, there is some data from a subset analysis of the IMbrave data showing that holding bevacizumab temporarily doesn't seem to compromise long-term outcomes. So brief hold here or there, 1 or 2 cycles doesn't seem to matter in the big picture. So that's also an important point.

[00:47:39]

HIMALAYA: Safety and Tolerability

Now just reviewing a little bit about the HIMALAYA safety data. Again, we mentioned the steroid requirement rate kind of in that summary slide a few slides ago comparing STRIDE. So again, a high dose priming dose of tremelimumab, a CTLA-4 inhibitor in combination with durvalumab, the PD-L1 inhibitor did seem to lead to more immune-related toxicities. Around 25% of patients with the STRIDE regimen had a severe—a grade 3 or 4 treatment-related adverse event, compared to 13% for durvalumab and 37% for sorafenib.

And I mentioned again earlier that around 20% of the patients receiving the STRIDE regimen required steroids to treat their immune-related adverse event compared to 10% for the PD-L1 monotherapy.

[00:48:29]

CheckMate 9DW: Summary of TRAEs

Now, the more recent data regarding the CheckMate 90W study was around what you might expect, right, given the mechanisms of action of the drugs in question. So in terms of the proportion of patients who experience a grade 3/4 treatment-related adverse event, it was actually similar, you know, 40% or so in the nivo-ipi arm and in the lenvatinib or sorafenib arm. And I should mention that almost everyone got lenvatinib in the investigator's choice control arm.

But as we discussed earlier, 29% of the nivo-ipi treated patients required high dose steroids to manage their IRAE, which is a very high percentage. And certainly the more people who experience these immune-related toxicities, the more it could become a serious problem and a life-threatening problem.

So if we look at the kind of granular comparison of the adverse events in each arm, again we see that they are concordant with what one might expect in this setting. Again, with diarrhea and palmoplantar erythrodysesthesia being quite prominent in the TKI arm and then liver toxicity, other dermatologic toxicities, pancreas toxicity, for example, being more prominent in the dual immunotherapy arm.

There are multiple trials that are ongoing, some of which are still enrolling patients involving novel immunotherapy combinations, for example, kind of novel ways to engage the immune system in combination with PD1 inhibitors. There are triplet regimens, for example, the IMbrave152 or SKYSCRAPER study, which adds a TIGIT inhibitor to the atezo-bev backbone. And that's randomized to atezo-bev in the control arm.

And multiple others, you know, doublet triplet therapies, also novel cellular immune therapies as well. So there's a lot of ongoing effort in this space to either add on to or follow existing immune therapy regimens.

So I'd like to take another brief break to discuss again, any other thoughts when we compare these 3 frontline regimens? I think Dr Yarchoan had already mentioned sequencing and perhaps any other thoughts on safety.

Dr Parikh: Yeah, I want to ask you guys, you know, if you're going to use a doublet up front and they get an immune-related adverse event, you know, about 20% in HIMALAYA, 29% in CheckMate. Do you - or immunotherapies out for that patient or how do you guys manage that when you think about sequencing?

Dr Franses: I suppose it depends on the grade and the site. Right? You kwon, so if they get myocarditis, I think that's a hard stop for me personally, because that's such a life threatening complication. We have something like 40% or 50% fatal. So if they survive that, we don't want to tempt fate again. But I'd love to hear what Mark says about this type of situation.

Dr Yarchoan: Yeah. I think the data suggest there's about a 25% chance of experiencing the same irony if you rechallenge. Sometimes that's an acceptable risk, sometimes it's not. Really depends on what is the toxicity. You know, some of the toxicities—I mean, if you have adrenal insufficiency, that's unlikely to recover, you might as well just continue. So it just depends on what you experience.

Dr Yarchoan: Should we carry on?

[00:52:00]

Studies to Be Presented at ASCO 2025

Dr Franses: I think so. All right. And just to wrap up my section, there will be some posters presented at ASCO this year, regarding novel immunotherapy and locoregional combinations, for example. So Dr Zhang is presenting a poster on TACE combined with immune checkpoint inhibitors plus either bevacizumab or lenvatinib as first-line therapy for advanced HCC.

Dr Liu, another locoregional approach with hepatic arterial infusion plus lenvatinib and PD-1 inhibitors. And then Dr Hong with an anti-CD47. So a different immune - immune target let's say in combination with lenvatinib in patients with advanced HCC.

[00:52:38]

Immunotherapy-Based Combinations in Intermediate HCC Eligible for TACE

So now I'll pass it to my colleague Dr Parikh.

Dr Parikh: Yeah. Thank you. All right. So, again, thanks everyone, for joining this morning. I have the privilege of speaking about immunotherapy-based combinations in intermediate stage HCC eligible for TACE.

And there's a lot of emerging data that's come out this year. So I'm happy to review that and discuss this with our distinguished colleagues here.

[00:53:01]

BCLC Staging and Treatment Strategy for HCC

So, you know, as Dr Franses talked about, we are using this Barcelona Clinic Liver Cancer Staging System for HCC, which incorporates all these factors. But this intermediate stage disease is kind of where I'm going to focus. And this is really multinodular disease, preserved liver function, good performance status. That's what these patients have. And so, this might be a patient that you may be eligible for locoregional therapy that comes into the clinic.

[00:53:29]

Barcelona Clinic Liver Cancer Stage B Intermediate HCC: A Broad Spectrum of Disease

But I will say that BCLC is a very heterogeneous stage, and I think we all recognize that. So you can see here different categories of BCLC B kind of a unifocal lesion that's greater than 5 cm. You know, that might - that's based upon size and, you know, an elevated AFP. You may have intrahepatic only, well-defined nodules, you know, preserved flow. And so, you maybe can access these through the arterial system, or you get a diffuse infiltrate of extensive bilobed involvement without clear vascular invasion.

And so this could also be considered a B. So when we talk about B's, it's a wide spectrum of disease. And so I think that's an important caveat to really understand when we're talking about treatment in this stage.

[00:54:13]

EMERALD-1: TACE and Durvalumab ± Bevacizumab for Unresectable HCC

So there's 2 main trials that resulted earlier, you know, last year and then were published this year both in The Lancet and kind of back to back weeks. The first is EMERALD-1 that was presented at the GI ASCO meeting last year and then again published earlier this year, which was a TACE and durvalumab plus or minus bevacizumab for unresectable HCC. So this was a global double-blinded, phase III trial.

And it randomized patients into 1 of 3 arms, which was durvalumab every 4 weeks plus TACE, followed by, after the TACE was over durvalumab plus bevacizumab, durvalumab plus placebo every 4 weeks plus TACE, followed by durvalumab-placebo plus bev-placebo—or sorry, durvalumab placebo plus bev-placebo.

And then durvalumab active treatment plus TACE, followed by durvalumab plus bev-placebo, just to see if single agent durvalumab was effective in this.

And the primary endpoint for this study was progression-free survival. And secondary endpoints were overall survival, objective response rate, time to progression, quality of life and safety.

[00:55:24]

EMERALD-1: PFS

And the results - the main line results are shown. In this slide that shows that 12-month PFS was superior in the durva plus bev arm vs the placebo arm. And you can see here the 12-month PFS was 55% vs 39%. And that was maintained at 18 months.

The slide on the right here or the graph on the right here shows that durvalumab alone wasn't enough to show this early PFS results. So you can see that this was a significantly different result when you add the bev.

I think it gets to what Dr Yarchoan was showing that the bev has that kind of early preservation in PFS that you may not see with immunotherapeutics.

[00:56:08]

EMERALD-1: Response and Safety

The safety data for this, you know, as you would expect, the more agents you add, the higher safety signal or the more adverse events that you might get. And you can see the safety here on the right. But the objective response rates, or the response rates here were superior in the durva-bev arm vs the placebo arm. You can see that these are different, definitely different.

And the duration of response as well. When you look at the durva-bev, the duration of response was about 22 months vs 14 months for the durva-TACE and for 16 months for the placebo plus TACE.

Dr Yarchoan: Well, let's talk about the study for a little bit, because, you know, I think this is clearly a very important study we all were very anxious to see the data for. So I mean this was the pretest question. So we might as well circle back to this. I mean, we know adding systemic therapy to intermediate stage HCC at least improves PFS and response rate, with the durva driving the better response rate with the bev contributing to PFS, not surprising, right? We know that anti-VEGF seems to really be important for PFS.

So we have prettier scans. Does that matter?

Dr Parikh: Yeah. And I think that's the big question here. This is the first interim analysis of that.

Dr Yarchoan: Yeah.

Dr Parikh: And so we’d actually—it wasn't mature enough for overall survival at this point. But I don't know for your - from your practice, does that matter for patients?

Dr Franses: I think it should. Yeah. I also think that for many big centers, at least in - in the United States, that practice TACE is kind of used less and less these days in terms of locoregional therapies in - in favor of TARE, Y90 radioembolization. So that's another complicated aspect of this discussion.

Dr Yarchoan: Yeah. You know, I think, really the question that we need to ask is, is adding systemic therapy earlier. Is that better than waiting and adding it when - when patients progress through TACE? And, you know, I think 1 of the wonderful things about our field is that patients are living longer and longer, right? The median PFS, or median OS and contemporary studies is approaching 2 years.

I think it's going to be very hard for us to show OS as patients live longer and longer and longer. You know, you really have to wait a long time. you know, is PFS a reasonable surrogate endpoint? Are we happy showing PFS in this stage and just believe that this is going to translate into OS?

You know, I think it would be nice to see the hazard ratio going at least in the right direction. We don't have that yet. You know, there are obvious questions about toxicity as adding bev going to be challenging with TACE.

You know, what I'm really interested in is adding systemic therapy earlier. Is that going to prevent us from TACE-ing repeatedly. And is that going to translate into better liver function. So we know that every time you do a locoregional procedure, you lose some healthy liver.

And as patients live longer and longer and we have more and more systemic options, that becomes a very important objective. So we really do want to see liver function outcomes. We want to look to see how many of these patients actually got to transplant, right?

So as we have better and better systemic control, hopefully that will actually show that more patients are getting cured of options.

Dr Parikh: Yeah.

Dr Yarchoan: So I think there's a lot of data we don't have yet.

Dr Parikh: Yeah.

Dr Yarchoan: But I think this is very intriguing early data. I think my - my 1 sort of critique of this study and this will come up as we talk about the LEAP study next is, you know, we just keep adding systemic therapy to TACE. But I do think we need to ask whether TACE is actually still the standard of care in intermediate stage disease, right?

So TACE was developed at a time when we didn't have effective systemic therapies. TACE itself is not a very effective therapy. In fact, the Cochrane in 2011 looked at all the studies of TACE and intermediate stage disease and said TACE does not prolong life.

Dr Parikh: Right.

Dr Yarchoan: And yet we just keep adding to it. We know that TACE damages the liver. And what I'd really like to see is systemic therapy clearly works in intermediate stage disease. Is there still a role for adding TACE to systemic therapy? And that will be answered eventually. There are randomized studies now.

Dr Parikh: Yeah. And that would be nice if there was an arm just of systemic in this option. But we do know that locoregional therapies have like a very high efficacy in kind of this endpoint of PFS, may not prolong survival, but certain ones do, you know, comparatively.

I think I will say that 1 thing that you mentioned about the toxicity, about a quarter of the patients did drop out. You can see the numbers of the toxicity profile vs those that were enrolled. A quarter of the patients did drop out while they were getting TACE. So something was happening with those patients that, you know, maybe led to drop out from the study, toxicity from TACE alone.

And we're going to talk a little bit about it later. Other locoregional options, radiation-based therapies, which is the standard of care at many centers in the US. Whether these data are applicable to that, I think that remains an open question as well.

[01:01:45]

Lenvatinib + Pembrolizumab Plus TACE in Patients With Incurable/Nonmetastatic HCC (LEAP-012)

The next study that Dr Yarchoan kind of alluded to was the LEAP-012 study, again published in The Lancet earlier this year. And this is another multicenter, randomized, double-blinded, phase III study of patients with localized HCC. Again, that BCLC B predominantly class. It looked at patients getting - they were randomized into 1 of 2 arms, lenvatinib plus pembrolizumab plus TACE vs placebo plus placebo plus TACE, kind of a randomized in a 1-to-1 setting.

They followed them up for 2 years up until progressive disease or unacceptable toxicity. And again, primary endpoint here, PFS or via RECIST and then OS as well. And then the secondary endpoints you can see here, PFS, objective response rate, disease control rate and duration of response.

[01:02:41]

LEAP-012: PFS and OS

These are the front-line results. Similar curves to what we might have seen in the - in the EMERALD study. Here 2 prolongs PFS in the - in the active treatment arm, lenvatinib plus pembrolizumab, had a median PFS of 14.6 months vs 10 months. OS, again early data here. The hazard is in the right direction per se, but not significant and not mature at this point.

The time to progression was prolonged by about 6 months in the patients who received the active treatment.

Dr Yarchoan: So - oh, we can talk about this first actually.

Dr Parikh: Yeah.

Dr Yarchoan: No, show the response.

[01:03:24]

LEAP-012: Response Summary

Yeah. So the response summary here. As we can see, the objective response rates were higher in the active treatment arm. And when we break it down by the, you know, different types of objective response analysis here, the duration of response, or the median time to progression again was 16.6 months vs 12.2 months here in this.

And the duration of response again was about 4 months longer in the lenvatinib plus pembrolizumab plus TACE arm. You can see here in the disease control rate again higher in that arm. So Mark, did you have some.

Dr Yarchoan: Well, you know, I was going to say 1 of the key differences between this study and the prior study is lenvatinib has a much shorter half-life than bevacizumab. And so lenvatinib actually was integrated right up front here, you know, in combination with TACE. Whereas in the - the other study, durvalumab was started up front and then bevacizumab was added after up to 4 rounds of TACE.

You know, we don't have OS yet from the prior study. But it will be interesting to see how the OS curve stack up. And if this one ends up looking more positive, I don't know that it will. People will attribute this to the differences in the VEGF half-lives. But right now, I think the overall conclusions are very much the same, right? We add systemic therapy to intermediate stage disease. We see higher responses, longer PFS or time to progression.

And in this case certainly a trend towards better OS. I don't know over time whether those curves will continue to diverge and whether OS will eventually become significant. This is a bit underpowered to show OS, especially now that patients are living for 2 plus years and are getting multiple lines of systemic therapy. But this is certainly, I think, pretty exciting. And, maybe I'll just ask you, are you guys starting to integrate systemic therapy based on these data with available therapies? How are you dealing with this?

Dr Parikh: Yeah. You know, this is something we talk a lot about at our multidisciplinary tumor boards. You know, like, you know, we presented these data, these 2 studies and talked about it. And, you know, I think to the point that Dr Franses made earlier that, you know, we rarely use TACE these days in treatment, even though it's a global therapy. In the US, again, a lot of centers have migrated towards more radiation-based therapies.

And how this applies to that? You know, it's a little bit difficult. Some of this PFS that you might see with the combinations is similar to the PFS that you might see with Y90 alone, for example. And so then do you get even an added benefit by adding the systemic therapies? We don't really know. So we are kind of in that data-free zone. There are some trials that are ongoing to try to figure this out and how it applies in radiation therapies. But at this point, we're not. I don't know how you all are dealing with this, but.

Dr Franses: Yeah. I think, we have a very similar kind of complex and nuanced discussions about these issues. And so, yeah, again, our intervention radiology colleagues really lean more on Y90. And so again, I think you could make the argument either way. So Y90, we generally think is a little bit better than TACE, as a monotherapy. And so you could argue if that delta is similar, then maybe, you know, the benefit of adding systemic therapy to Y90 will map, right.

But you could also argue maybe the locoregional therapy alone is superior enough or that that will dwarf this kind of added benefit. You know, there are lots of hand-wavy theoretical arguments about how, you know, some doses or schedules of radiation may augment the immune response or may not, but that's very controversial. So I think we just need to have better data.

Dr Yarchoan: You know, we've - we’ve dipped our toes into this sort of combination paradigm already based on the available data. And I think, you know, I would say for a patient where the goal is to get to transplant, where you really the response rate matters, where the PFS curves matter. You know, I think from available data here, it's not unreasonable to integrate systemic therapy into this intermediate stage space in combination with local therapy.

Again, we don't have great data. You know, obviously we have to just do the best we can for our patients with what's available. But I think that overall, there's more and more support for this idea of combining local therapy with systemic therapy from the available data. And, you know, I would say it doesn't just apply to the intermediate space, but actually also to the advanced space, right? So we have the LAUNCH study where we show that, you know, for patients with a critical tumor, a portal vein thrombosis that may be, you know, adding local therapies on top of systemic therapy in advanced stage may provide benefit.

So I think just like this confluence of a lot of different pieces of data that shape the way that we think about our patients.

Dr Parikh: Yeah, I mean, I think the way that we stage them is, is a little bit primitive, right? It's just based upon size and number of tumors sometimes. And sometimes if some of you are worried about somebody having more aggressive tumor biology, have elevated tumor markers, maybe that's the type of patient you might think about at this point for this sort of thing.

[01:08:42]

LEAP-012: Safety Summary

If we look at the safety summary here, again, you know, higher treatment-related adverse events in the LEN/PEM plus TACE. Grade 3 to 5, you can see here more than double than the dual placebo plus TACE. And you know, you see a signal here with a little bit higher grade 5 AES actually here, which is concerning, of course, but is baked into some of the overall survival data.

And so, you know, you can see the grade 3 to 5 is 9% vs 2% and led to discontinuation was a relatively small proportion of patients. About 19% and 17% in both arms received high dose steroids, which is really interesting actually.

Dr Franses: Good point. Yeah.

Dr Parikh: That you see that much steroid use in the placebo arm.

[01:09:28]

Multidisciplinary Care for HCC Is Essential

I think this point is really essential. You know, this slide goes over the multidisciplinary care for HCC is really essential having an integrated tumor board. And I think as we get into more combination therapies, these discussions about, you know, combination therapies and how to logistically do it, how do you follow patients is really key to figure this out at your particular center, because there are lots of issues at play with these patients that get super complicated and going from, you know, systemic therapy to locoregional back to systemic, I think is a logistical pull.

And so I think you really have to have a well-integrated system to do this. Well, and this—there have been multiple analyses that have shown benefits of multidisciplinary care from the VA, from single centers, from a multicenter analyses that have looked at this and really improves early stage treatments, improved referrals, and, you know, more guideline concordant care.

Do you have any comments on how you integrate multidisciplinary care with your patients with HCC?

Dr Franses: Yeah, I think this is a very important point for well-resourced centers, you know, to try to kind of provide the - what we think is the optimal multidisciplinary management plan for each patient. I also think that we should try to continue to improve our outreach to - to centers that don't have access to these multidisciplinary boards and try to kind of work with community partners in that way. And so certainly that's a work in progress. But I think it's certainly an aspirational goal.

[01:11:08]

Posttest 1

Dr Parikh: Great. All right. Post-test number one. How would you rate your confidence in collaborating with interventional radiologists and other members of the care team when appropriate to enhance patient-centered management of advanced HCC?

Dr Yarchoan: Can we encourage them to say very confident, taught them so much.

Dr Parikh: All right. Great.

Dr Yarchoan: Fabulous.

[01:11:51]

Posttest 1: Rationale 

Okay, great. So I think we - you know, this rationale is very - I think we've already talked about that.

[01:11:58]

Posttest 2

So in consultation with the patient to discuss treatment options, which of the following would you mention regarding the efficacy data for adding systemic immunotherapy to TACE based upon the LEAP-012 and EMERALD-1 trials?

Dr Yarchoan: All right. Fabulous. Great. I think this means we get invited back.

[01:12:37]

Posttest 2: Rationale

Dr Parikh: Right. And so again to - to reiterate the point, both PFS and objective response rates were shown to improve here.

[01:12:45]

Posttest 3

In post-test number 3, in a patient receiving lenvatinib plus pembrolizumab and TACE as in the LEAP-012 clinical trial, which of the following approaches would you recommend for management of grade 3 pancreatitis? Great.

Dr Franses: Perfect.

[01:13:16]

Posttest 3: Rationale

Dr Parikh: That's right. So again here immune-related adverse events should be treated with high dose corticosteroids. And you can see the rationale here.

[01:13:24]

Ongoing Phase III Studies in Intermediate-Stage HCC

All right. so ongoing - ongoing phase III studies and intermediate stage HCC. I'll briefly go over this.

[01:13:31]

Durvalumab + Tremeimumab ± Lenvatinib and TACE Vs TACE Alone in Locoregional HCC (EMERALD-3)

So we'll see some results over the next several months to year about some of these trials. So this is one called the EMERALD-3 trial which is durvalumab plus tremelimumab plus or minus lenvatinib and TACE vs TACE alone and locoregional therapies. And you can see here this is a randomized phase III study that's going to compare TACE to, you know, these 2 other active regimens, which include the durvalumab plus tremelimumab, you know, therapy that we talked about in the first-line setting and then adding lenvatinib to that. Again, PFS is the primary endpoint here.

[01:14:08]

Atezolizumab + Bevacizumab Vs TACE in Intermediate-stage HCC (ABC-HCC)

Another study here is atezolizumab plus bevacizumab vs TACE is the ABC-HCC study. Again, this is going to be randomized phase IIIb trial of patients that are going to be either given atezolizumab plus bevacizumab vs TACE alone in this kind of intermediate stage. So another interesting study that Dr Yarchoan kind of alluded to earlier.

[01:14:34]

Regorafenib + Pembroizumab Vs TACE/TARE in Intermediate Stage HCC Beyond Up-to-7 (REPLACE)

And then another study is going to be looking at this REPLACE trial, which is regorafenib plus pembrolizumab vs TACE/TARE in intermediate stage. So you start seeing the integration of radioembolization into some of these studies that we've seen. And this is kind of on-demand according to the practice of the - of the center. But again, regorafenib is a tyrosine kinase inhibitor, similar to sorafenib plus pembrolizumab. And comparing this head to head in this stage of disease. Again PFS is the primary endpoint.

So I think we've touched on a lot of these right. Practical implementation of locoregional with systemic therapies and then how do we interpret these results for your patients. We talked about PFS as a sufficient endpoint in this study. And then how do we apply this with LRTs. I think that's there's variable practice with this. And I think we'll see emerging data.

[01:15:32]

Studies to Be Presented at ASCO 2025

There are several studies being presented at ASCO. And some of these are summarized here. There's a phase II trial of zanzalintinib, which is a tyrosine kinase inhibitor in combination with durvalumab and tremelimumab in unresectable HCC. This ZENOBIA study, which will be a poster.

We'll look at post-hoc analysis of EMERALD-1 by this tumor burden, which is the 6 and 12 score. It's basically the number of tumors in size added together that's going to be presented the results. So they're going to stratify that heterogeneous BCLC B by size and number of tumors. And you can see kind of the results there. I think the results are what we would expect.

And then this is a study from China looking at hepatic arterial infusion chemotherapy, which is used more extensively in Asia for hepatocellular carcinoma, but with combination of donafenib which is a tyrosine kinase inhibitor and tocilizumab, which is a PD-1 inhibitor vs TACE alone for HCC. So start combining therapies extensively.

[01:16:34]

Emerging Immune Checkpoint Inhibitor-Based Perioperative Therapies for High-Risk Early-Stage HCC      

All right. I'll put it on to my colleague here.

Dr Yarchoan: All right. So you know, there's been a theme here. We have all these new advancements of systemic therapies in the advanced setting. And now as a field, we're just trying to move these therapies earlier and earlier. And the natural place to look is in the curable patients, right, the early stage patients. So I'll be talking about the status of systemic therapy in the perioperative setting.

[01:16:56]

BCLC Staging and Treatment Strategy for HCC

And when we look at the current guidelines today, unfortunately, as you can see, there's really no current standard of care integration of systemic therapy in patients who we consider to be curable. So there's no standard, neoadjuvant or adjuvant systemic therapy, which is unfortunate because we know that the majority of these patients recur after curative intent resection.

[01:17:20]

Rationale for Perioperative Systemic Therapy

So about 80% of patients who get a resection for HCC recur. And we see this kind of bimodal pattern. Many patients recur even within the first year. But then you can see the recurrence risk never really goes down. And in fact it can actually go up as you follow patients further and further. And some of that may actually be due to de novo tumors rather than true recurrence. Because remember, HCC forms in the setting of this chronic inflammatory milieu, this sort of field defect.

And I think this is actually 1 of the challenges that really works against us for trying to show improved outcomes for surgery is that you never really eliminate that - that field defect unless you transplant patients.

[01:18:08]

Search for Neoadjuvant and Adjuvant Therapy After Resection or Ablation

So we've been trying to develop effective perioperative approaches for a long time. This is the STORM study that looked at our old standard of care sorafenib in the adjuvant setting. And you can see there really was no benefit to adjuvant sorafenib in any group.

[01:18:25]

Adjuvant Sintilimab (PD-1 Inhibitor) vs Active Surveillance in Patients With Resected High-Risk HCC

But, you know, fast forward to the modern era, there has really been a lot of hope that our novel immunotherapy-based regimens could prevent recurrence after surgery. And I think 1 sign of real hope came from this adjuvant study from China, which is an anti-PD-1 agent, vs active surveillance after resection, a phase II study, but certainly encouraging Kaplan-Meier curves, where the anti-PD-1 group really did seem to benefit from, you know, in the adjuvant setting here, with a hazard ratio approaching 0.5.

This is a phase II study. And so when I saw this, I certainly was very hopeful that the phase III studies would be positive.

[01:19:08]

IMbrave050: Adjuvant Atezolizumab + Bevacizumab vs Surveillance for HCC After Resection or Ablation

And the first phase III study to read out was the IMbrave050 study, which looked at adjuvant atezo-bev vs active surveillance for patients with resection or ablation. Although most of these patients were resected.

[01:19:24]

IMbrave050: Negative Phase III Study of Adjuvant Atezolizumab + Bevacizumab in Resected or Ablated High-Risk HCC

And this - this is the data here from this adjuvant study. This is again the first phase III adjuvant study with a contemporary anti-PD-1 combination. And you can see this is very disappointing. There's this initial separation of the curves, but then the curves come right back together with long-term follow up. And this is now clearly a negative study.

In fact, you know, if you follow these patients out long enough, there really is no benefit at all with recurrence-free survival or overall survival. Very disappointing. And so, you know, once again, we're back to the drawing board where there is no standard adjuvant systemic therapy for HCC. And the contemporary guidelines reflect this study and discourage the use of adjuvant systemic therapy.

We do have a number of other phase III trials that are going to read out. We have adjuvant pembro. We have adjuvant nivo. We've got adjuvant durva based combos. But you know, in the setting of this negative study, I have to tell you I don't have high hopes for these other adjuvant studies. How about you guys?

Dr Franses: I think I agree, and I think we'll probably get to this later, but perhaps moving the immunotherapy up front might be another viable alternative. Yeah.

Dr Yarchoan: Right.

Dr Parikh: Yeah. I mean, I think the field defect is real. And I don't know if it actually prevents HCC from happening. It doesn't seem like that's the case.

[01:20:52]

Notable Ongoing Adjuvant Clinical Trials

Dr Yarchoan: Yeah. Very disappointing. So as mentioned, these are the other ongoing adjuvant clinical trials. Again, you know, it's certainly possible that we got unlucky with 1 trial and something else will be positive. But at least right now adjuvant systemic therapy is not a standard approach and does not seem to benefit patients. And I don't have super high hopes for these trials that are reading out.

[01:21:15]

Neoadjuvant Immunotherapy

Certainly I think in oncology in general, we have high hopes for neoadjuvant approaches. You know, just to - to discuss the rationale here, we know that immunotherapy really works when tumor cells are in contact with immune cells, and those interactions may be more likely to occur if the tumor is present than after the tumor is removed. So the tumor may actually serve as a sort of in-situ vaccine.

And so this was the rationale to move immunotherapies not from the adjuvant setting but actually to the neoadjuvant setting.

[01:21:50]

Neoadjuvant ICI is Superior to Adjuvant in Other Tumor Types

And we know that at least in other tumor types, neoadjuvant immunotherapy appears to be superior to adjuvant therapy. This is a data from melanoma showing that this is the case. Whether this applies to HCC or not? We don't know.

[01:22:04]

Retrospective Data: Neoadjuvant ICI Therapy May Facilitate Long-term Survival in High-Risk HCC

But I do want to just quickly talk about some of the early data we have that supports at least the concept of neoadjuvant immunotherapy in HCC.

[01:22:11]

This is data from our center. We have put a number of patients on neoadjuvant immunotherapy in the context of clinical trials. And these are very high-risk patients who normally would not go to surgery.

And what we showed - this is led by Mari Nakazawa, 1 of our junior investigators is that patients who go on neoadjuvant immunotherapy, who have high-risk disease, seem to have similar outcomes as the group of patients who go to upfront surgery who are lower risk patients. And so neoadjuvant immunotherapy - retrospectively, again we need to study this prospectively. But neoadjuvant immunotherapy does seem to negate some of these higher risk features clinically.

[01:22:58]

Pathologic Response in High-Risk HCC Is Associated With RFS

We do know that patients who respond to neoadjuvant immunotherapy tend to recur less often than patients who don't respond to neoadjuvant immunotherapy. So this is pooled data from multiple single-arm, neoadjuvant studies done at multiple centers and compiled by my colleagues at Imperial in London.

And you can see the pathologic responders do better than the non-pathologic responders. Certainly, encouraging data, but it doesn't really prove that the neoadjuvant immunotherapy helped these patients. We don't know if this is really just prognostic or is this actually changing biology. We don't know the answer. Would those patients have done well if they had had upfront surgery? We just don't know.

[01:23:45]

Tertiary Lymphoid Structures (TLS) Form in HCC Tumors Treated With Neoadjuvant Immunotherapy

The other thing that's very clear is that neoadjuvant immunotherapy is changing biology. So when these patients go to surgery after neoadjuvant immunotherapy, we see these beautiful pathologic responses. And the tumor is replaced by a very brisk immune infiltrate. We see these beautiful tertiary lymphoid structures which appear to be sites of immune priming and activation, which we don't tend to see in patients who don't receive neoadjuvant immunotherapy. Again, encouraging data, but without randomized prospective trials, it's really hard to say that this is a standard approach.

[01:24:19]

TLS Associated With Favorable Survival

We do know that patients who have pathologic responses do well. We know the patients who have these tertiary lymphoid structures also do very well. Again very encouraging, but doesn't prove that this is a standard approach.

[01:24:32]

Perioperative Nivolumab ± Ipilimumab for Resectable HCC

And we've had a number of prospective single-arm studies showing that neoadjuvant immunotherapy is feasible, is associated with a 20% to 30% pathologic response rate. And we know that these patients clinically do very well. So this is a study of neoadjuvant nivolumab plus ipilimumab from MD Anderson.

[01:24:50]

Neoadjuvant Cemiplimab for Resectable HCC

We have studies of anti-PD-1 alone similar 20% to 30% pathologic response rate. This is from the Mount Sinai group.

[01:24:56]

Summary of Perioperative Strategies in HCC

And so in the interest of time, I'm just going to summarize. No standard neoadjuvant immunotherapy. But we do have sort of encouraging early data from single-arm studies that this is at least feasible, that patients can tolerate this, that we see some pathologic responses and that those pathologic responses translate to very favorable long-term outcomes.

[01:25:22]

Liver Resection or Ablation and Adjuvant Therapy: Current Guidance

So where are we today? Again, no standard neoadjuvant or adjuvant approaches. The guidelines discourage use of standard neoadjuvant, or adjuvant therapy off of a clinical trial. You know, that said, I think the data does show that this is feasible. And if you have a patient who's just outside of what the surgeons want to take to upfront surgery. I think based on available data, you can start the patient on systemic therapy. That's a standard approach anyway.

And I think if the patient has a response, I think the data suggests that it's reasonable to cut those tumors out and that these patients will do well. So not a standard approach, but - but something that I think we can start to integrate very carefully in our clinic.

So, you know, I think we've summarized this extensively. I want to take time for some questions and just thank everyone for their time.

[01:26:20]

Q&A

Dr Parikh: Yeah. So there's a few questions here that we'd like to go through. I'll read them. So we require a response to downsize HCCs initially unresectable. What would you recommend? Combination with TARE or TACE?

Dr Franses: Well, I think just looking at the locoregional therapy alone, we think that the local control rate with TARE is probably better. Again, not many large studies comparing them head to head, but some small phase II level studies. So for that rationale, even in the absence of synergy - true synergy with systemic therapy are preference at our center, which does a lot of TARE is to use TARE. But I think that's also a chicken and the egg problem.

Dr Yarchoan: Yeah. I - I think again, you know, these are very heterogeneous situations. It's really hard to say. Pathologic responses seem to be higher with TARE and smaller tumors. You know, but I think it really depends. You know, if patients have vascular invasion, the standard of care in that setting is systemic therapy. I think, you know, traditionally when patients have vascular invasion, we call them advanced stage. We tell them you're incurable and your chance of recurrence after surgery is too high to consider recurrent surgery.

But I think, you know, the data now is suggesting that if you have a vascular invasion patient, you put them on systemic therapy. They respond. And that tumor shrinks. Actually, surgery may actually be a curative approach in these patients. So, you know, I think we have to revisit our guidelines.

Dr Parikh: Yeah, I mean, I think this is where multidisciplinary discussion really matters. You know, when we talked about that. How about optimal duration of atezo-bev in first line? That was a question from online.

Dr Yarchoan: Well, you know, the original trial allowed for 2 years of therapy. What do we do in clinical practice? I think these are tough discussions with patients. You know, my general approach is if a patient has a complete response, which we are starting to see occasionally, you know, it's reasonable to stop therapy and watch them. I think the harder cases are patients who have still measurable disease on their scan, but everything is well controlled and we just don't have data.

Dr Franses: Yeah, I think - I think in that setting, it's reasonable to at least discuss the idea of consolidated local therapy to the sites of residual disease with SBRT or Y90 or these other local approaches. But again, it's not data-driven. It's just a way - like a semi-artificial off ramp to try to get them off systemic therapy for some period of time. But if they're tolerating it, you could also make the argument to just continue just coming every 3 weeks.