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My name is Dr. Joseph Franses. And today, I and my distinguished colleagues will be talking to you about Redefining HCC Treatment in the Immunotherapy Era. We'll be providing expert insights and discussing multimodal innovations and coordinated care for optimal outcomes across the disease continuum.

I'm an Assistant Professor of Medicine at the University of Chicago in the section of Hematology Oncology. I'm joined here by my colleague, Dr. Neehar Parikh, who's an Associate Professor in the Division of Gastroenterology and Hepatology at the University of Michigan, and Dr. Mark Yarchoan, Associate Professor of Medical Oncology in the division of GI Malignancies at the Sidney Kimmel Cancer Institute at Johns Hopkins University.

Dr. Parikh: Let us go back to the advanced stage. We did not really talk about biomarkers of treatment response or things that you would use, but how does PD-L1 status impact the choice of first-line regimen?

Dr. Franses: It does not for HCC. There was a biomarker analysis of the IMbrave150 data published in Nature Medicine a couple of years ago, using bulk RNA-seq transcriptomics to try to develop a signature. When they conditioned the differential expression from responders versus non-responders, so CR plus PR versus SD versus PD, they did develop a 10-gene signature, a lot of immune genes related to that. Then, unfortunately, at the end of the paper, essentially their immune gene signature was shown to be very, very highly correlated with just CD8 IHC. Just T cell infiltrates. We do not routinely get that. We do not really order that for pretreatment biopsies. I would love to hear what Dr. Yarchoan thinks.

Dr. Yarchoan: I think we have no truly clinically actionable biomarker for front-line therapy. In HCC, the only standard biomarker is AFP for ramucirumab and subsequent therapy lines. It is not for lack of trying. We have tried to develop biomarkers for so long.

I think clearly, patients who have more inflamed TME, more CD8 T cells, a higher immune score, which has been scored many ways, seem to derive more benefit from immunotherapy-based combinations. But that is not very helpful because everyone is getting immune-based combinations anyway.

I think what we really need is who should get ipilimumab-nivolumab or durvalumab- tremelimumab or who should get atezolizumab-bevacizumab. We really do not have anything actionable in that space.

I think the one thing we should talk about as a group on the topic of biomarkers is the story about NALFD or MASH-associated HCC, and whether that in any way impacts systemic therapy. There was this concern a couple of years ago that maybe patients with MASH derive less benefit from immunotherapy-based regimens, based on mostly preclinical data.

That story has really receded somewhat as we have more and more clinical data showing that patients with MASH seem to have very similar responses to immunotherapy as everybody else. Etiology right now is not a biomarker that, at least in my practice, I use in any way. Either of you know?

Dr. Franses: No. Agree.

Dr. Parikh: I think what we see consistently in the systemic trials is that patients with viral hepatitis do have higher response rates, for whatever reason, in some of these studies, especially with the tyrosine kinase inhibitors. We saw that with sorafenib and lenvatinib.

The immunotherapeutics, that story has gone away a bit. It is also difficult to categorize patients really cleanly. A lot of patients with viral hepatitis probably have fatty liver disease. What exactly is metabolic liver disease? Characterizing the severity and things like that are really difficult. I think these are not clean lines for a lot of these patients.

Dr. Yarchoan: It does seem like in a lot of these global studies, the patients with Hep B derive more benefit from whatever the more intensive systemic therapy is. I wonder how much of that is that they tend to be younger patients with less advanced cirrhosis, a less competing mortality from their underlying liver disease. I do not know how much that is playing a role.

Dr. Franses: Is it a prognostic biomarker? That almost certainly is true, whether or not there is additional predictive value? Hard to say.

Dr. Parikh: Yeah. Another study is regarding a grade 3 pancreatitis case that we discussed. Would you recommend high-dose steroids even in the absence of symptoms?

Dr. Yarchoan: Yeah.

Dr. Parikh: It may be getting to how you screen patients for irAEs, AEs,. When you are having somebody on systemic therapy, do you send things that patients may be asymptomatic for, or how do you screen?

Dr. Yarchoan: Yeah, this is a tough case. Actually, pancreatitis in particular is not a classic irony where there are great data for what to do. I think asymptomatic elevations and lipase is not something that in my practice I really do much with. I do not tend to check it.

Dr. Franses: Right. For all the trial patients, it is drawn as a standard expanded array of lab work. I tend to check thyroid in addition to the standard metabolic screening. That is essentially it.

Dr. Yarchoan: Yeah. Whether or not troponin monitoring has a role, I do not know. I think the data is not super clear. I do not tend to check ACTH levels and cortisol levels.

Dr. Parikh: 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 intermediate stage 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 five centimeters. 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 - you know, 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.

So there's two main trials. The first is EMERALD-1 that was presented at the GI ASCO meeting, 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 one of three arms, which was durvalumab every four weeks plus TACE, followed by, after the TACE was over durvalumab plus bevacizumab, durvalumab plus placebo every four 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. Twelve-month PFS was superior in the durva plus bev arm versus the placebo arm. And you can see here the 12-month PFS was 55% versus 39%. And that was maintained at 18 months.

Durvalumab alone wasn't enough to show this early PFS results.

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.

But the objective response rates, or the - the response rates here were superior in the durva-bev arm versus the placebo arm. And the duration of response as well.

When you look at the durva-bev, the duration of response was about 22 months versus 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.

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 that's the - I think that's the big question here. This is the first interim analysis of that.

Dr. Parikh: And so we’d actually - it - 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: 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 one 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 - 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 - 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.

I think my - my one 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 - and you know 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 one 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 versus 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 I think the point about - 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.

The next study that Dr. Yarchoan kind of alluded to was the LEAP-012 study, again published in The Lancet. 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 one of two arms, lenvatinib plus pembrolizumab plus TACE versus placebo plus placebo plus TACE, kind of a randomized in a one-to-one setting.

They followed up - followed them up for two 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, PFS, objective response rate, disease control rate and duration of response.

These are the front-line results. Similar curves to what we might have seen in the - in the EMERALD-1 study. Here two prolongs PFS in the - in the active treatment arm, lenvatinib plus pembrolizumab, had a median PFS of 14.6 months versus 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 six months in the patients who received the active treatment.

The objective response rates were higher in the active treatment arm. And when it's - 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 versus 12.2 months here in this. And the duration of response again was about four months longer in the lenvatinib plus pembrolizumab plus TACE arm.

Dr. Yarchoan: I was going to say one 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 four rounds of TACE.

You know, we don't have OS yet from the prior study. But it will be interesting to see how the – 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 two 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 two 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?

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, whether or not - I mean, 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 - the benefit of adding systemic therapy to Y90 will map, right.

But you could also argue maybe the - 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 - 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 you're – some of you’re 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.

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, 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.

The grade 3 to 5 is 9% versus 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. 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 - you know, 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 a good - I mean, it's certainly an aspirational goal.

Dr. Parikh: I think there are a couple of questions that we want to get through here. Do you have any criteria for selecting TARE over TACE?

Dr. Yarchoan: It is interesting. If you look at the randomized studies of TARE, if this were a drug, I do not think it would be approved. We have had multiple negative trials of TARE versus sorafenib, negative, TARE in all sorts of settings. Randomized trials are truly negative. TARE was finally approved based on, believe it or not, a retrospective data set. The LEGACY study, even though it has a name, is a retrospective trial. No drug that I can think of would ever be approved in that fashion.

I think I am willing to say that there is reasonable evidence that TARE has a higher pathological response rate than TACE. I think that for a patient with a small tumor, TARE can be ablative and TACE is usually not ablative. Whether this makes any difference at all in a patient with multifocal disease? I do not think is truly established. I think many centers have moved more towards TARE than TACE. I do think anecdotally it is better tolerated. That is part of the equation here. I would say TARE is more widely used in the United States, based largely on expert opinion, but without the robust data that we would love to see to really back up that practice.

Dr. Franses: Speaking of situations in which we have little data, what about SBRT? What is your center's practice using that as another option for local regional approaches?

Dr. Yarchoan: I would actually push back and say there is strong data for SBRT. We have randomized trials now showing equivalent outcomes as microwave ablation in early-stage disease, with a higher local disease control rate. This is grade 1 evidence in contrast to TARE. I think SBRT is a great additional local therapy to have in our armamentarium. Are you guys getting a lot?

Dr. Parikh: Yeah. We use a lot at our center, especially for tumors that cannot be easily thermally ablated. Either they are a little too big or they are at the dome or next to the gallbladder, in certain areas. SBRT seems to be safe and effective in those cases with very high local control rates.

I think the idea is to bridge a patient, these local regional options are beneficial, as Dr. Yarchoan said that sometimes we just do not have the evidence to show that it improves survival. But in a setting where you are trying to get somebody to a more radical therapy like liver transplantation, they can be a very effective and local control of both of these therapies, radiation-based therapies.

I think we actually now have some SBRT data from the Toronto Group in advanced-stage disease, albeit with tyrosine kinase inhibitors. There was a benefit when you adjust for disease severity in that study that was published.

Dr. Franses: Sorry, I probably should have specified a little bit more carefully. I meant more SBRT versus Y-90. That is what I was thinking.

Dr. Parikh: That is an unknown.

Dr. Yarchoan: I think, in general, in oncology, sometimes we have these dramatic Phase III trials with huge separation of the curves. Immediately, something is adopted. Sometimes there is just this slow adaptation, just based on anecdotal experience that something might be a little bit better.

I think radiation-based therapies versus TACE falls in that latter group that over time were just a lot of centers have slowly adopted more and more radiation-based therapies, either TARE, SBRT, because anecdotally they seem to be well tolerated, have high pathologic response rates, and high disease control rates. I am not sure we are ever going to get that slam dunk, beautiful separation of OS curves that we love to see with things that are widely adopted.

Dr. Parikh: Let us talk about one of the questions in high-risk early HCC.

Given the discordant data for immune checkpoint inhibitors in early disease space, what is your thoughts on why IMbrave050 was negative compared to other studies, like adjuvant sintilimab, showing efficacy with ICI? Do you think is a population difference? Is it just a different ICI? The effect might be different, or what do you think the issue is here?

Dr. Yarchoan: Sintilimab study is a Phase II trial. The atezolizumab-bevacizumab is a phase III trial. It is hard for me to imagine that the difference in agents is driving the difference in outcomes. I do wonder, as there are larger studies, that we will have some clarity about whether there is a role for adjuvant immunotherapy.

Dr. Franses: Yeah. We see this all the time, confirmatory phase III trials not showing putative benefits shown in smaller studies that may have had just random differences that were unaccounted for in the arms.

Dr. Parikh: I think the nice thing is that there is more data going to come out in this space. As mentioned earlier, we are going to really get a very strong sense of what the role of adjuvant therapy is here. If they are all negative, I think we will really know the truth here. It is because of the preponderance of evidence.

Dr. Yarchoan: There are obviously differences in the patient populations with these trials. But even though sintilimab was a study conducted in Asia, most of the patients on the IMbrave050 study were also included in Asia. I do not think that is really what is driving the differences.

Dr. Yarchoan: My concern, sintilimab is a anti-PD-1. atezolizumab-bevacizumab, PD-L1 with a VEGF. VEGF has not really panned out in the adjuvant setting in a lot of tumor types, but it is hard to imagine it was detrimental. For me, at least, it is hard to imagine that PD-1, PD-L1 matters in this context because it has not mattered across other tumor types and similar settings. We will see. We have large phase III trials of anti-PD-1, like the pembrolizumab study and nivolumab study, so we will know soon.