The use of Immunotherapy in unresectable Hepatocellular Carcinoma (HCC)

Intro This podcast is for healthcare professionals only and is supported by an independent educational grant from AstraZeneca. Speaker 2 Welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. Today we're kicking off a four part series on Hepato cellular carcinoma HCC. We'll start off with first line treatment options, then we'll switch gears to focus on second line treatment options. Thereafter the last two discussions, we'll touch on the evolving space of intermediate ACC. Coming back to this, our first session, let's talk about IO and IO combinations in advanced unresectable ACC. To cover this, we're joined by Doctor Rachna Shroff, a medical oncologist and the Chief of Hematology and Oncology at the University of Arizona Cancer Center. Rachna, welcome. Speaker 3 Thank you both so much for having me. Speaker 4 Thanks so much for joining us. Diving into our topic which is first line treatment options for hepatocell or carcinoma. First line treatment options for hepatocellular carcinoma We have seen few options evolve through the course here. Before committing to any of our patients with this treatment, it is important to keep medical comorbidities in mind along with liver function. If you don't mind touching on the front line treatment options where this is rather evolved and the most most likely option that we have been utilizing is all immunotherapy based now. Speaker 3 Absolutely. It's such an exciting and different landscape for treating hepatocellular carcinoma or liver cancer. You know, we've really moved into the immunotherapy space as you as you suggested and it is a really complex disease because the underlying liver cirrhosis really plays into how we approach these patients and how they do in terms of overall prognosis. But in terms of newly diagnosed advanced hepatocellular carcinoma, we really have immunotherapy as the mainstay. And that really was first brought about with the EMBRAVE 150 data. So this was the study that looked at atezolizumab and bevacizumab, a monoclonal antibody against VEGF. That's bevacizumab with a checkpoint inhibitor and that is the atezolizumab. And that was compared to what was our standard of care at the time, which was serafinib. And you know the study initially came out in 2020, but then there was subsequent additional longer term follow up and data that was then published. And with the updated analysis, which was a median follow up of about a year and a half like 15 1/2 months. The atezalismab and bevisizumab arm did continue to statistically significant significantly improve overall survivals. The median overall survival in this arm was 19.2 months compared to serafinib which was 13.4 months. Similarly, we saw an improvement in progression free survival as well from 4.3 months to 6.9 months and an objective response rate of 30% with the Atezobev arm compared to about 11% with Serafinib. So just all the key efficacy endpoints with longer term follow up, that was proof of principle that in patients with preserved liver function. So all of these studies are child QA cirrhosis patients, meaning early stage cirrhosis that there is an immunotherapy option with otezlaizumab and bevacizumab. But like you mentioned, we also have additional options now and that's what's really making this interesting, a little bit more complicated, but somewhat exciting. And so the second option that really came about was based on the Himalaya study. So the Himalaya study was a large global study as well that looked at a combination dual immunotherapy approach. And that was what's historically called the STRIDE regimen, but basically is 1 dose of tremolimab, which is an anti CTLA, 4 with dirvalimab. And it was actually initially A3 arm study. So it was the STRIDE regimen, Tremidorva versus single agent, DORVA versus serafinib, but the study was really looking at overall survival of the STRIDE regimen versus serafinib. And so when the Himalaya data first came out, it was a positive study. But what was really exciting at ESMO just this year, a couple months ago, we saw the updated five year overall survival. And again importantly with longer term follow up, we are seeing continued statistically significantly improved survival with the Durva tremie versus serafinib. And I just want to remind everyone that the STRIDE regimen is just a single dose of the anti CTLA 4. So it's tremolimab times one with DORVA followed by DORVA alone. And with this regimen, the median overall survival with STRIDE with 16.4 months versus 13.7 months with serafinib. But as we typically look for an immunotherapy, what was really impressive about this was that separation of the curves. And so when you look at that Kaplan Meyer with the longer term five year OS data, the landmark 60 month overall survival with the STRIDE regimen 19.6% at the 60 month mark versus this is 9.4%. So one in five patients still alive at the five year mark with advanced hepatocellular carcinoma, which is just incredible. And so it's just really kind of proof of principle that with newly diagnosed Hepato cellular carcinoma patients, we have options both with the VEGF plus IO approach and then a dual IO approach. And then again, just to kind of complicate but make things equally exciting is we now have a second option in that dual IO approach. And that's based on the Checkmate 9 DW study, which was basically a study that looked at again, anti CTLA 4 with a checkpoint inhibitor, nivolumab with ibilimumab compared to investigator choice. So that here people were given the option of giving lenvatinib or serafinib because by the time this study was designed, lenvatinib was an option for frontline treatment. And so in this study, this was the anti CTLA 4 was given up to four cycles and so it was a little bit more of an anti CTLA 4 compared to the Dorva tremie approach. And then nivolumab was continued and the primary endpoint was overall survival. And again at ESMO this year, we kind of saw updated median OS data with a median OS of nivo, it'd be a 23.7 months versus 20.6 months in the investigator choice arm of Limbatinib or serafinib. And again separation of the curve with a three-year OS landmark rate at 38% versus 24%. So again, a dual IO approach with a little bit more use of the anti CTLA 4, kind of more, more longer term ibulumab versus the Durva tremie. So really three options. And you know, it's hard to know exactly where to start with kind of teasing it out. But what's really great is, is depending on your patient, you can hopefully find an immunotherapy option for them. Speaker 2 Wow, these are exciting times. What? You started off by talking about the landscape shifting. Russ know you touched on this. Most of the comparator arms were serafinib or limbatinib because we did not have any better options. And now here we are. Be it because of Iron Braid 150 or Himalaya or Stride regimen or Checkmate 9 DW, we have a few options. You touched on limbatinib. Recently we also saw a combination of pembro with limbatinib here, which is indeed a negative study. But coming back to our available options, Rachna, how do you decide one over the other? How to decide between IMBRADY and Himalaya Who's the right patient? What are we looking at in our? Speaker 3 Clinic, I think that's it's such a good question. I mean, at the end of the day, there are some small nuances in terms of eligibility between I'm brave versus Himalaya, for instance, in terms of patients who were included with, with VP4, basically portal vein involvement, which was, you know, tends to be a poor prognosis, if you will, if there's kind of main portal brand portal lane branch involvement. But the honest truth is, is in clinical practice, I I think it really just kind of comes down to potential side effects and or kind of the nuances of how often patients want to come and, and things like that. So for instance, with the atezo Bev regimen, with the, with the study, everybody had to have an endoscopy because with an anti VEGF, you worry about the risk of variceal bleeding in known in patients with known cirrhosis. And so, you know, there are some people who may have varices that are at risk of bleeding. There are some, I, I hear from a lot of community physicians. Sometimes it's just hard to get an endoscopy quickly and to get a look at the varices to see if there's anything of concern. And so in those patients, you know, it's stride and easier option because you're not worried about that bleeding risk. I think there's a lot of people who really appreciate the one time dose of the tremie and then, you know, coming back every four weeks, which is, you know, unfortunately with a lot of our hepatocellular carcinoma patients, there's a lot of other psychosocial components that go into their management. And so transportation issues, availability and time off work, I mean these are real world problems that we deal with. And so I think some of those things are really the ones that play in now. Checkmate. You know we don't have it FDA approved yet, but I would imagine it may or may not be soon I would think. And there again there is the anti CTLA 4 priming that happens a little bit more regularly. And so it'll be interesting to see what the uptick is. And you know what, we'll, I know what we'll talk about safety shortly, but it'll be interesting to kind of see if people, again, from a real world perspective, just prefer that one time anti CTLA 4 so that they can then just get their one drug every four weeks. I, you know, it'll be, I think that remains to be seen. Speaker 4 Well, thanks so much for stressing the importance of at least the three options, but two of them are FD approved and we'll have to just wait for how Nivo EP turns out. When talking about a Tiso Bev, as you stressed that we have stronger data when it comes to portal venous thrombosis On the contrary to that is durbotremi with one single dose of tremi. Longer term A5 year survival data is looking promising as you stated as well. Now in community, we have to get used to the side effect profile with what you stated with Bevisysmap concerns of bleeding while with Durbotremi we are aware about the immune related side effects. Clinical Pearls Any important clinical pearls that you'd suggest for us to keep in mind especially with durbotremi? And it is? Speaker 3 There's what we we saw in the trials and then there's the like actually clinically relevant and and kind of issues that we deal with. And I will say and I, I don't know what you're all experience has been, but with Atezo Bev, you know, the, the, the study mandates and thus our, our chemo orders, our, our, our treatment orders basically have us check for instance for the urine protein. And you know, at the end of the day, proteinuria we know is a known side effect from bevacizumab, but a lot of our HCC patients with cirrhosis already have proteinuria, right. So how much I put stock in some of those things that were obviously important treatment related adverse events that were looked at in the study. I think there's no, it is not as much of A concern as the things related to risk of bleeding as well as, you know, hypertension that can come from bevacizumab because any sort of general hypertension in an underlying patient with cirrhosis can be very can become clinically relevant just depending on what happens with the the hepatorenal components to hypertension. But in general, you know, I, I will say, I mean, we've been using tyrosine kinase inhibitors in these patients and lowered. Do those have their own set of problems? And so I think it's a relatively well tolerated regimen. Similarly, Durba Treme, you know, yes, we obviously are always worried about immune related adverse events, both with the Atezzo from atezo Bev as well as with a dual IO approach like stride. But the honest truth is, is that there was really no surprising safety signals that came out from the Himalaya study and the immune related adverse events were were relatively rare and and relatively mild and, and manageable with you know, steroids or treatment interruption and things like that. And then the updated five year data just kind of again showed that there was really no new signal safety signals that came out. I think the biggest concern obviously with immunotherapy in patients who have hepatocellular carcinoma and again have underlying cirrhosis is you know, hepatitis like an autoimmune hepatitis type of picture. And thankfully, at least in the I am Brave and Himalaya data, it was actually relatively rare. And I will say in clinical practice, when and if I see it, usually just a usually it's mild and it's, it's not requiring treatment discontinuation or steroid use or things like that. So, you know, I think that's the beauty of the immunotherapy changes that we've seen with the landscape because not only are they great in terms of efficacy, but they're overall pretty well tolerated. Speaker 2 And again, the side effects, be it from a Tiso Bev or are not trivial, but in community at least, we're so used to using these drugs now, dual checkpoint inhibitor as we use it for lung cancer. Of course, we've used a Tiso Bev now for a period of time. So I do think that there is comfort around these two regimens as well. Rachna, are you swayed one way or the other by the cause of underlying cirrhosis or ACC viral versus any other etiology? Are you picking one treatment over the other based on that? Speaker 4 And also just to add to that, so sorry before you answer. And does Child Pew rather dictate your treatment options here as well? Speaker 3 You know, I think those are again really good questions and I think the short answer is, is I, I don't right now in terms of etiology and making those decisions. I mean we know that there is a potential signal that you know viral hepatitis may be a little bit more immune responsive. But the honest truth is, is that none of that has been prospectively validated. It's all been looked at in kind of exploratory analysis that are not powered to answer those questions, right. And so to me, especially in the US where nowadays our etiology is really more fatty liver metabolic syndrome leading to more of a Nash picture and, and, and our navelty and, and Nash and and then subsequent HCC development. And you know, Hep B has never been a huge problem. Any hepatitis C is curable now. You know, I think in general thankfully in clinical practice I haven't had to sweat it I guess too much. It's really interesting. I mean I know we're not talking about Cam Revo, but the CARES 310 data with camrylizumab and rivacerinib where you know all majority done in Asia without very hepatitis B heavy population. You know, I mean we had do not have that FDA approved because there is questions of you know how much that viral hepatitis component really drove this. And so I think the jury is still out. But as of right now in the day-to-day, no, I don't, I don't use that as a determining factor in terms of child Pew. You know, I, I think kudos, I, I believe the a Tezo Bev investigators are doing a child Pew up to B7 study, looking at a Tezo Bev prospectively. And I believe there's maybe a couple investigator initiative trials that are also looking at stride and up to a child Pew B7. Because again, when you talk about the real world, I mean, most of my patients, we're lucky if we get a child QA, most of them are these, these bees that are teetering, you know, and thankfully, at least in my anecdotal experience and from talking to other investigators around the country, patients tend to do well. I mean, the honest truth is, is that so much of this is that fine balance between how much the Hepato cellular carcinoma is taking over liver parenchyma and contributing to the worsening liver function versus the underlying cirrhosis and that chronic kind of slow burn if you will in terms of liver health. And so, you know, I think I think that is the right trials to be doing is let's look in, in the patients that we actually see as opposed to these, you know, marathon runners, these child PUA type of HCC patients. But as of right now, I again I I case by case make the determination. But Child Pugh B sevens with massive ascites look a little bit different than Child Pugh B sevens because they have a slightly elevated INR from underlying liver function. Speaker 2 Right in the real world, we're actually extrapolating this data day in day out. A good B7. We treat them as Child Pugh A and we offer these treatments even though again, the initial studies were done on better liver function, but like you mentioned, retina a poor B7, you have to be very cautious on how far you're going to push them. While we're talking about all our treatment options, I'm going to push a little more on the Checkmate 9 DW as well. Dual Checkpoint Innovator NevoAP Not at the approved right now as you mentioned more CTLA 4. Is this another Me too combination when I have tried regimen at least in my practice, even if this was to get approved, I don't think this will change my practice. Am I missing anything? Can you touch on this a little, if this dual checkpoint innovator is another Me Too drug or how do you see that will shift the practice? Speaker 3 It's such a great question. I mean, right now a lot of people are touting that again, it's an apples and oranges comparison, but the median OS is, is quote, UN quote better than what we've seen so far and that the objective response rate, which is like around 36% is quote UN quote better than what we've seen before. But I agree with you. I mean, you know, when you look at the treatment related adverse events at the end of the day, you know, grade 3-4 on the Nevo AP arm was about 41% of patients. And when you look specifically at immune mediated hepatitis, that was a little bit more pronounced than we have seen in other the other IO studies. And so a lot of that kind of underlying Hepato biliary disorders as they classified it makes me a little nervous. I mean, I think it was around 11 percent of patients had grade 3-4 Hepato biliary issues. And that's, that's not insignificant in, in our HCC patients because coming back from that can sometimes be really difficult to, to help our patients kind of reverse that kind of liver, liver damage, if you will. So I again, I think that real world applicability and using it in real in real, in real situations will help us. I know that a lot of, you know, people who are not me who are community oncologists and are, have been using Nevo Ippy for years in, in other diseases might be more comfortable with it. But I don't, I don't think we can underestimate the impact of cirrhosis and underlying liver disease on giving Nevo Ippy. So I'm going to be a little bit, yeah, cautious, I think. Speaker 4 While talking about what the future looks like, Rich now what do you think is on the horizon for the treatment of unresectable hepatocellular carcinoma in frontline? What is on the horizon for the treatment of unresectable hepatocellular carcinoma in frontline? First of all, there's a lot of really interesting add on approaches, whether that be, you know, other immunotherapy modulators like anti TIGIT and then you know what what adding in a checkpoint plus TIGIT plus, you know that that sort of approach could be. There's obviously still interest clearly from if you look at the CARES 310 and even some of the other data that came out of ESMO at you know, a TKI and an IO combination. Like you mentioned LEAP was disappointing, the Lenva Pembro combination and so was the Cabo Atezo combination. But I think there's still people looking at some of these approaches. To me the most interesting space is, is really that combination multimodalities approach as well. So there's a lot of interest in understanding that things like liver directed treatments like radioembolization and trans arterial chemoembolization can help. And you know, it's already being looked at like with the Emerald One study looking at intermediate stage, we even in an advanced set setting, we know that the morbidity and mortality that comes from HCC is from the disease in the liver, right? And so is there a benefit even in advanced HCC to combine these multi modality approaches with now these IO approaches? I think there's a lot of interest in that. And then of course there's, you know, a lot of hope for the the self therapy approaches car TS and and looking at specific potential targets, if you will, that are are pervasive in hepatocytes. So I think there's a lot going on in the front line space and you know, it's AII jokingly say that it's now a good problem to have that we have a wealth of of options and hopefully that allows for patients who don't qualify for one drug or one regimen to have another regimen option available to them. Speaker 2 You know, future certainly looks exciting in the community. We need to make sure that we give access to our patients to these clinical trials that will potentially become new standard of care treatment in the near future rush, not just before we close. Any final thoughts or key takeaways for our listeners treating unreceptable HCC? Key Takeaways My key take away is I jokingly say that like 15 years ago when I started being AGI oncologist, there was no way I was willing to treat HCC because all we had was serafinids. And now it's, it's just such a different space. I mean, people are living longer, they're living well, while they're living longer, they're sometimes dying of other causes as opposed to their HCCI mean it's just such a great time to be involved and, and to watch this landscape change so rapidly and, and for so in, in such an impactful way. So I mean, it's just there's so much more coming. Speaker 4 Exciting times and immunotherapy has truly been the been the treatment of choice here and continues to evolve with some combinations here. Thank you so much doctor for sharing your thoughts with us today. For our listeners, let us go over a quick recap on today's discussion and remember this is the first of four part series of Paracel or carcinoma. In today's discussion with Doctor Rashna Ashraf from University of Arizona Cancer Center, we had a chance to focus on first line treatment options in unresectable paracellular carcinoma. Particularly are available options for IO and IO combinations. Keeping patients medical comorbidities and their underlying liver function status is so critical. Speaker 2 In first line, we have options of tyrosine kinase inhibitors or apisobab based off Iron Brave 150 or duvalumab with tremidlimab based off Himalaya or Streitstein. Each available option comes with its fair share of unique side effects and recognizing this is equally important. Thank you for joining us. Make sure to check out our other discussions in this series over the next few months. We also look forward to seeing you in person at GI ASCO 2025. We are at the Oncology Brothers. Speaker 1 If you enjoyed this podcast and want to find out more than please look for the Oncology Medical Conversation Podcast under the account of Core to add medical education. Also, don't forget to rate this podcast, subscribe to our channel and share it with your colleagues. Thank you for listening and see you next time. This podcast is an initiative of Core to Add and developed by HTC Connect, a group of international experts working in the field of oncology. The views expressed are the personal opinions of the experts and they do not necessarily represent the views of the experts, organizations or the rest of the HTC Connect group. For expert disclosures on any conflict of interest, please visit the Court Red website.