BackTable / VI / Podcast / Transcript #402

Podcast Transcript: Immunotherapy in HCC: Evolving Treatment Paradigms

with Dr. Tyler Sandow, Dr. Edward Kim and Dr. Terence Gade

In this episode, Dr. Tyler Sandow (Ochsner Health) interviews interventional radiologists Dr. Edward Kim (Mount Sinai) and Dr. Terence Gade (University of Pennsylvania) about the future directions of hepatocellular carcinoma (HCC) treatments, specifically focusing on the adoption of precision medicine and multidisciplinary approaches. You can read the full transcript below and listen to this episode here on BackTable.com.

(1) The Landscape of Systemic Therapy for Hepatocellular Carcinoma (HCC)

(2) The Science of Immunotherapy

(3) Establishing a Multidisciplinary HCC Practice

(4) Combination Therapy Options in HCC

(5) Who Benefits From Combination Therapy?

(6) The Role of Adjuvant Immunotherapy in Early-Stage HCC

(7) Safety of Systemic Therapies in HCC

(8) Approaches to TACE & Multifocal Disease

(9) Treating Large Central HCC Tumors

(10) The Future of HCC Management & Interventional Oncology

Stay Up To Date

Follow:

Subscribe:

[Dr. Tyler Sandow]
All right, this is a special podcast episode today sponsored by AstraZeneca and hosted by the Society of Interventional Oncology, SIO. We have two incredible guests in front of us, basically guys that I would consider part of the Mount Rushmore of interventional oncology, and I'm a bit of a fan boy being able to talk to these guys. I remember watching as a resident at SIO probably in 2016 when both of you were speaking, might have been SIO or SIR, but I was just amazed at how knowledgeable, how well presented you were.

I guess, first off, I'm going to say welcome, Drs. Edward Kim and Dr. Terence Gade. It's a pleasure to have you. It's a pleasure to be part of this. I'm going to stop for a second and allow you guys to introduce yourselves.

[Dr. Edward Kim]
Thanks, Tyler. Ed Kim here from Mount Sinai Hospital in New York. It's an honor to be on this show and to be on this podcast with both Tyler and Terence.

[Dr. Terence Gade]
Thanks very much, Ed. Thanks, Tyler. Really excited to be here. It's a real honor. I'm Terence Gade. I'm an interventional radiologist at the University of Pennsylvania.

[Dr. Tyler Sandow]
Awesome. All right. Can we do a quick icebreaker? I feel like it's just going to make things easy for me. Now you guys might be, I don't know if you're baseball fans or not, but what I always consider to be one of the key things to every baseball game is the closer's intro music. Now, I've thought about if I were in your shoes, if I were the closer, what my intro music would be. This would be like if you were walking into the Angio suite, what intro music are we listening to?

[Dr. Terence Gade]
For me, it's got to be White Stripes, Seven Nation Army.

[Dr. Tyler Sandow]
I like it. I like it.

[Dr. Edward Kim]
I'm a big baseball fan right now just because my hometown team are the Phillies, but I've always liked Enter Sandman, for closing.

[Dr. Tyler Sandow]
I picked that for you. I was going to say–

[Dr. Edward Kim]
All right. I don't know if that's for IR though, man. I don't know if that's the best for IR or doing a procedure.

[Dr. Tyler Sandow]
Dude, I was going to say that is definitely Ed Kim's. That is Ed Kim's song, is Enter Sandman. That is the Mariano Rivera entrance song. That's awesome.

[Dr. Edward Kim]
That's right.

[Dr. Tyler Sandow]
Awesome. Awesome. Look. Tell me about your IO practice. How many people are involved on the IR aspect of things? We'll dive deeper into the multidisciplinary team, but is it a core group of you that do the majority of the IO? Terence, I'll let you lead off.

[Dr. Terence Gade]
Here we're spread across three institutions. We have about 19 IRs, and I'd say about a good third to a half of the group are consistently involved in the IO practice. We have people who specialize in certain areas, certain diseases, but we're doing a lot of neuroendocrine, a lot of HCC, starting to do a lot more MSK work as well.

[Dr. Edward Kim]
Yeah I mean for us, usually about three or four from our group of about a dozen IRs total are ones that really focus on interventional oncology. More specifically in the liver, we have a large HCC practice. I would say the vast majority of our interventions are for HCC cholangio and metastatic disease as well, but we're focusing mainly on HCC. Then our team is really a team approach within IR with, obviously, our technologists, our nurses, our medical students, residents, and the attendings are all really vital to our operations.

Also not to exclude our physician extenders. A big component of what we do is also our finance section that gets pre-authorizations and approvals in a timely fashion. For instance, people who need expedited TARE, we can see them in our office hours and have them on the table for mapping within a week, and then treated within two weeks from seeing them in office hours. So a big team. Then we'll also, obviously, Tyler, will go into the multidisciplinary team, which is also a vital component of our care.

(1) The Landscape of Systemic Therapy for Hepatocellular Carcinoma (HCC)

[Dr. Tyler Sandow]
Yeah, totally. Both of you guys are incredibly well-experienced, which is why we have you guys talking about this. We're going to highlight really the treatment of advanced HCC now, more about the immunotherapy aspect and the IR's role in the immunotherapy game. As we transition to that, I was hoping that one of you guys could give me a background story on systemic therapy for HCC. Terence or Ed, if y'all want to take it over.

I know from a systemic therapy standpoint, I would say that we're still in the infancy of systemic therapy, quite younger than a lot of systemic therapies for other types of cancers.

[Dr. Edward Kim]
Yeah, I'll start off. Historically speaking, the SHARP and Asia-Pacific trials really put Sorafenib on the map for HCC, where there really wasn't anything available in the advanced stage population. That had a good run for about a decade. In terms of the trials, there was like approximately a three-month benefit. I wouldn't say anyone would admit saying that they were excited about putting patients on Sorafenib.

I think that for that decade, a lot of local regional therapy was in play in that advanced stage and sometimes really pushing the limits in terms of local regional therapy. Then when CheckMate 040 came out with nivolumab, there was a lot of excitement. Even though it was a phase one dose escalation study, there was a lot of excitement, especially in this new era of immune checkpoint inhibitors in immunotherapy.

It's a very exciting concept that your body can prime itself and attack tumors like it would any type of infection, for instance, and treat it as a foreign body. This created a lot of excitement. Then subsequent trials read out that were positive. We can go into some of those, and Terence maybe can expound on those. IMbrave150 and HIMALAYA and also Lenvatinib really provided positive trials with meaningful survival benefit in the advanced stage.

[Dr. Terence Gade]
Yeah. I think to build on that, that timeframe, it's really been up until 2008, 2009 with the SHARP and Asia-Pacific trials, like Ed said, we really had very few drugs really making it into phase two trials for HCC. It was a really challenging time. But the escalation in what we've learned about systemic therapy over the past decade is really remarkable. I think really the IMbrave150 and HIMALAYA trials really mark a point of departure where we start to understand how powerful combination therapies can be.

I think that's been borne out in the systemic therapy trials, but it really provides us a real jumping off point when we start to think about local regional therapy in combination with a variety of these different systemic agents, including immunotherapies.

(2) The Science of Immunotherapy

[Dr. Tyler Sandow]
Yeah. Thank you. Terence, I'm going to have to put you on the spot because I remember you actually did this at an SIO presentation. I think this was like seven years ago, but you went into the basic science about how immunotherapy works. Would you be willing to do that now or am I putting you too much on the spot?

[Dr. Terence Gade]
No, I'm happy to talk about what I know. Immunotherapy, as we think about it in clinical medicine, really involves two primary forms of therapies. Those include PD-1 and PD-L1 inhibitors. PD-1 inhibitors largely target T-cells and the PD-L1 inhibitors largely are targeting the tumor cells themselves, breaking up that interaction through which tumor cells can suppress the immune response when the PD-L1 ligand binds to the PD-1 receptor on the T-cells.

There's a lot of discussion about which of those is more effective. There's very limited data really about that, although there is one trial I think in colorectal cancer which demonstrates that PD-1 inhibitors are more effective. Could make some sense because you're really targeting the T-cells themselves and the other functionalities that PD-1 may have, whereas with PD-L1 inhibitors you're targeting primarily tumor cells. But as we're starting to learn, combination therapies are really powerful, so really targeting both sides of that axis can make a lot of sense.

[Dr. Tyler Sandow]
As I understand it, I guess PD-1 and PD-L1, that marriage when it takes place tends to basically shut down the immune response. It basically causes it to blind itself away from an attack. Is that correct?

[Dr. Terence Gade]
That's right. Essentially, it's an interaction that's designed for where tumor cells can actually suppress the typical responses that immune cells have when they encounter foreign bodies. It's a sort of derivative of a wound response.

[Dr. Tyler Sandow]
Nice.

[Dr. Edward Kim]
I would say it's interesting, Tyler and Terence, though, because when you look at the Phase III RCTs that I've read out, we can certainly go into trial design, but the PD-1s have been negative and the PD-L1s have been positive. So what's your take on that, Terence?

[Dr. Terence Gade]
Well let's talk about which studies we're talking about in particular.

[Dr. Edward Kim]
CheckMate 459 and also Chemo.

[Dr. Terence Gade]
Very interesting in the context of HCC. Single agent therapies have not been very effective. I think that that's been the real transition within HCC, so I'm not sure. It's hard to know why those differences exist, but I think that, by and large, what we've learned is those combination therapies, that's really what turned the tide in terms of understanding how immunotherapy can be effective in the treatment of HCC.

There wasn't a lot of enthusiasm around CheckMate 040 because there really wasn't a big response, and I think the other responses have been limited as well and really paled in comparison to HIMALAYA and IMbrave150. I'm not sure I understand why one might be more effective than the other, but by and large I don't think, as monotherapies, either of them was particularly compelling.

(3) Establishing a Multidisciplinary HCC Practice

[Dr. Tyler Sandow]
I think that's going to be an important thing for us to come back to down the road when we talk about, especially that you highlighted it, Terence, where we talk about a single agent having less of a response, but maybe if there was some type of primer that helped boost the immune response down the road. I think that we might be able to talk about the nice play of IR and oncology in the immunotherapy game.

Before we go down that road real quick, let's talk about the HCC practice. Ed, I'm going to start off with you. How do HCC referrals come into your practice?

[Dr. Edward Kim]
It's probably going to be similar between Terence and myself and yourself as well, Tyler. We're part of a large liver transplant institution, and so, for instance, today I had multidisciplinary office hours with our hepatologists, with our surgeons, and our transplant coordinators, and so we see a lot of our patients together, either who are within transplant criteria or those that are ineligible for transplant, potentially downstaging, but also all the palliative patients as well.

Just across the street from us are our medical oncology colleagues and our radiation oncology colleagues, and we really offer the patient to see us all in one day, if feasible, and so that really helps individuals that come from a long distance because they have a plan of care formulated on that day, and so our referrals, the largest of our referrals are from our transplant team.

Now, we also have a separate surgical oncology group, and obviously, medical oncology also refers these patients to us. All HCC patients in our institution, our health system, are presented in our multidisciplinary tumor board once a week, and we go usually through 20 to 30 patients in an hour and formulate a plan for these individuals. So once that is set, various surgeons will refer based on when our office hours for the four of us that focus on interventional oncology each have days, Monday, Tuesday, Thursday, Friday, in multidisciplinary office hours, and we'll see patients side-by-side during those days.

[Dr. Tyler Sandow]
Terence, what about you? Is it a similar process over there at Penn?

[Dr. Terence Gade]
Yeah, it's a similar process. Obviously, multidisciplinary tumor boards playing a really important role in how we see our patients, especially as the healthcare system grows. This is happening with a lot of healthcare systems where they're expanding out into the community and trying to really have a focal or center for cancer care, and in particular for us, it's been HCC, and so that multidisciplinary tumor board is that opportunity for providers from across the region to bring their cases and have those discussions and then identify opportunities for us to become involved in care.

We also have a multidisciplinary clinic that occurs on Fridays where we're seeing patients along with our oncology, hepatology, and surgical oncology colleagues.

[Dr. Tyler Sandow]
You both have said a catchword for me, and I was waiting to hear it, the multidisciplinary clinic. Obviously, we're talking about the Mount Sinai and the Penn, like the Ohio State University. We're talking about the top places in the country to do IO. The multidisciplinary clinic, I think, is the way it should be done at the best places in the world. Obviously, not everyone has that same access. That's where I think IRs role in the multidisciplinary tumor board is the closest you can get to being part of an integrated team.

As we talk about what a multidisciplinary clinic is, just so that we're all on the same page, that's when you're seeing patients alongside the oncologist, and you both have said that, alongside the hepatologist, the oncology team, the surgical oncology team, the interventional radiology team, everybody sees that patient in tandem. You share clinic space. That's not always how it's going to be for the private practices of the world or places that aren't as well established as what you guys have and what you guys have built.

So that certainly, for places that are not at that level, I think it really, the importance of the tumor board is critical. You both said y'all do weekly tumor boards. Is that correct?

[Dr. Edward Kim]
Yeah, that's correct. I will say one disclaimer on behalf of Tyler and Backtable for the Michigan fans out there. Tyler didn't mean–

[Dr. Terence Gade]
I'm very happy you brought that up. As a Michigan grad, I was very disappointed to hear.

[Dr. Tyler Sandow]
Yeah.

[Dr. Edward Kim]
There it is.

[Dr. Tyler Sandow]
I knew I was ready to rub somebody the wrong way. Here we go. I told you. Ed, it didn't take me very long. We're only 20 minutes into this and I'm already going for it. All right. Ed, you talked about this. In your tumor board, y'all have somewhere between 20 and 30 patients. You tackle it all in an hour. Obviously, you're incredibly organized. To be able to talk about a patient in two to three minutes, to turn them over rapidly like that. How does it run? Who leads it? What's the IR role in the tumor board?

[Dr. Edward Kim]
Yeah. So all of the patients have to fit into a template sheet. It's an Excel spreadsheet with their brief history, date of birth, obviously their information, lab values, ECOG performance status, and then proposed plan of care. Then we go over that imaging now in a virtual format that's obviously encrypted. Interventional Radiology and myself and also one of my partners, Kirema Garcia-Reyes, we both take turns leading the tumor board from Interventional Radiology.

Then my colleague, who's the head of Hepatobiliary Surgery, Myron Schwartz, also leads the tumor board. These cases are presented. We've been doing it for so long that most of the cases to us are quite straightforward. Plans are formulated within two minutes' time for very straightforward cases. Sometimes you have cases that require a little bit more discussion, especially now with systemic therapies in place, specifically checkpoint inhibitors. We'll get, obviously, into that discussion later on in this podcast. It's really led by IR and Hepatobiliary Surgery transplant.

[Dr. Tyler Sandow]
Terence, what about y'all?

[Dr. Terence Gade]
Yeah. Similarly, it's an integrated effort involving multiple specialties. Obviously, transplant surgery, hepatology are playing really central roles in collaboration with IR. Radiology, diagnostic radiology is a very big part of it. Having our diagnostic colleagues to help us interpret the images and really provide their expertise is also incredibly valuable. It really does take a village, so to speak.

[Dr. Tyler Sandow]
I love that. Okay. Hopefully, I've praised you guys enough. If I haven't, I will say that you guys have built or helped establish and continue to establish some of the greatest interventional oncology practices in the country. Like I said before, we don't always have the same resources, the same information, the same data. How do we do our best to get to the same level as you guys are?

Let's say from a private practice standpoint, what can a private practice interventional radiologist do to help bring their game up to the same level that you would see at a place like Penn or like Mount Sinai?

[Dr. Edward Kim]
I would say that's a difficult question for us to answer, Tyler, just because we are in an academic center. I can certainly give my perspective and my view to our private practice, our community hospital partners, but it won't translate because I've never been in that area. I would flip that question actually to you, Tyler. You're a humble individual, but you have built up quite the practice yourself.

I would ask you, I know you're moderating, but how did you do it? How did you build up the practice that is quite impressive yourself down in New Orleans?

[Dr. Tyler Sandow]
Well I was jealous of the Ed Kims and the Terence Gades of the world, and so I decided that I wanted to be like that. No, I will say this. For us, it required a lot of-- and one, I should take almost zero credit for this. I had some incredible partners that came before me and then some incredible partners that actually lead our practice that really deserve all the credit when it comes to where we are.

But we try to do everything we can to integrate ourselves with the whole hospital team, whether it be transplant surgery, surgical oncology, hepatology, podiatry. You can find things anywhere. I think the mindset that we all have to get to is that we want to be helpful regardless of the situation. I think as long as we always have the patient's best interest in mind, even if it's something we can't do, we start to build relationships that become the cornerstone to integrating ourselves into the full team.

I will say a lot of the success that we have involves stuff that we did with transplant surgery that had absolutely nothing to do with HCC. It had to do with hepatic artery stenosis work. That led to more research roles where we started looking at our HCC outcomes. We used to be a TACE-heavy place, and then we realized that we were probably better suited trying to chase Ed Kim's LEGACY and RASER studies. We're trying to be like the best of the best. That has helped boost our practice.

Being able to track our outcomes. That has helped integrate us, I should say. For us, we don't have the same multidisciplinary clinic that you guys do. Our presence in the tumor board is critical. We try to go, all of us try to attend as much as possible weekly. All right. Thanks for flipping that back on me. I'm supposed to be the one asking all the questions. We're going to, we're going to flip back now. Now I'm going to try to pimp you with all the good stuff.

[Dr. Terence Gade]
To build on that just a little bit, I think that there's a lot of content out there that's available for everyone. I think that definitely I have had the blessing of being at a center where there's a really well established program. Obviously I like what you said, Tyler. I think, at some level, certainly everything that's happening at Penn has been built by others and I've really benefited from that.

I think that, being in those multidisciplinary tumor boards and those multidisciplinary clinics, the importance of being up to date on the latest guidelines and the latest data is so essential. I think that content is being generated by our societies. I'll definitely put a plug in for

[Dr. Edward Kim]
a bit much for this podcast, unless you think otherwise, Tyler.

[Dr. Tyler Sandow]
No no, we're good.

[Dr. Edward Kim]
Yeah. I would say that the gist of it is that both of these phase three RCTs showed a benefit in those combination therapies. Now you can choose one or the other. I've had many discussions from medical oncologists from various practices all over the world in terms of what they choose. Some of it is driven by reimbursement and social healthcare, and some of it is driven by patient factors.

For instance, individuals who have varices may not get atezo-bev because they need to get scoped and that might delay the care, and if they have varices, they caution against using it. There's a little bit of controversy now saying that it doesn't really matter, but when you read the trial, that's a problem.

[Dr. Tyler Sandow]
Right.

[Dr. Edward Kim]
So maybe they trend more towards Durva/Treme in that situation as opposed to atezo-bev. Either way, these are now firmly incorporated into the BCLC algorithm for the advanced stage population and potentially creeping into what is now being categorized as the advanced intermediate. There's also Lenvatinib, which is a tyrosine kinase inhibitor as well that can be used as first line. But I think most individuals right now are gravitating towards the checkpoint inhibitors.

[Dr. Terence Gade]
I think that's borne out by the latest ASCO guidelines for HCC as a combination therapy, as first line.

(4) Combination Therapy Options in HCC

[Dr. Tyler Sandow]
Awesome. All right. Real quick, IMbrave150 and HIMALAYA, the two of the pivotal trials, I would say for all of us that are probably not as well-versed in all of the literature, there, Terence said before, SIO has incredible, incredible educational opportunities, I'm going to shamelessly plug, there's a private practice symposium that's going to be hosted on the back end of SIO this year on January 29th for all attendees.

It's dedicated to the guys that don't have the same access to the data and to the literature that some of the best in the world get. It's a way to help bring us all to the same level or as close to the same level as we can so that we can all be versed in what we need to do, how to bring those cutting edge treatments and techniques and ideas and opportunities to our patients, wherever we are. Another shameless plug, private practice symposium for SIO. It'll be on January 29th, following SIO that weekend.

All right. Now we've talked about combination therapy, and I think we can call combination therapy two different things. We can call it systemic, two different types of systemic combination therapy. What I've always cheated and called combination therapy was combination therapy with maybe a local regional therapy and another form of systemic therapy. Now I'm talking to two incredible interventional oncologists. I'm going to steal this opportunity to learn from you.

I know what you're going to say. I'm going to pause you for a second. I'm going to let Terence lead off. So Terence, tell me why you would choose one local regional therapy over another, especially when it comes to combination and where you would use it.

[Dr. Terence Gade]
Okay. That's a great question. To start off thinking about local regional therapies between the local regional therapies, I think that's something that as a field, we really need to tout the fact that we have multiple therapies to treat a single disease. It makes us very unique. I think it's really about finding the right therapy for the right patient. We've started to think about how we determine that? I think part of that is some of the underlying biology of the tumors.

We know from our own studies and from some of the literature that's out there, and I will say that there needs to be more data around this, but it appears that the molecular subtypes of HCC will respond differently to different local regional therapies. We tend to think about TACE first at Penn, but that's informed by things like those molecular subtypes. For example, the Wnt-Beta-Catenin-Mutant HCCs tend to respond well to TACE. So as I'm thinking about that, and when I have that molecular data, we do use that to think about how we're treating these patients.

We're thinking about a variety of factors in the context of the stage of the disease, obviously there's great data for early stage disease and response to radioembolization. That's where we see the lion's share of our TARE coming from. Then, depending on the patient's clinical history, we will decide between TARE and TACE for those intermediate, and in some cases advanced stage disease.

We have been informed by the TACTICS and LAUNCH trials. That data I think is really powerful and important for IOs to consider when they're thinking about integrating systemic therapy with local regional therapies. We have been able to engage our hepatology and oncology colleagues around the use of Lenvatinib or Sorafenib with TACE. I don't have hard numbers for that, but we have seen some good responses in that context. That's sort of how we're approaching it, trying to really tailor the therapy to the patient.

[Dr. Tyler Sandow]
So I'm going to piggyback on that. You talked about the molecular subtypes of HCC. I assume that that's probably with the core biopsy. Is that correct?

[Dr. Terence Gade]
Yeah, that's where we're getting our data at this point. Obviously there are emerging technologies that are going to allow us to get molecular information a little less invasively, but still, that's where we've been able to get the data. Obviously there is some controversy around that biopsy of HCC is not part of standard of care. I understand that in as much as we don't have a ton of information about how those molecular subtypes are going to inform therapy, but as some of this data comes out, including some of the data that we've been able to generate through some of our clinical research studies, I think it's going to be more and more important.

You're starting to see this question being asked and addressed in the oncology world when people are thinking about systemic therapies, because again, these are not harmless therapies. The IMbrave150 had more than 50% grade three adverse events. You only got to get a response in 30% of your patients. These therapies need to be applied judiciously. There's more and more data about how different molecular subtypes are going to, or how those molecular subtypes shape the immune microenvironment and what the implications are for immunotherapy in that context.

[Dr. Tyler Sandow]
Do you biopsy every patient that presents with HCC or is there a selection process that goes through to determine whether or not you're going to biopsy versus not biopsy?

[Dr. Terence Gade]
We're trying to biopsy as many patients as possible. I think it really does come down to the choice of the operator, how they feel about the location of the lesion, the safety of that procedure and how they think about treating the patient. I would say in the context of the research we're doing, we are trying to enroll as many patients in that biopsy study as possible. I'd say that still the majority of patients are not getting biopsied.

[Dr. Tyler Sandow]
All right. I know the answer to this, Ed, but I got to ask it. Okay. Why would you choose one local regional therapy over another when trying to consider some type of combination with another systemic immunotherapy agent? What would you choose? I think I know the answer, but what would you choose?

[Dr. Edward Kim]
It's not as easy as you're making it out to be, Tyler. I would say that first going back to the IMbrave150 and the HIMALAYA trials, absolutely positive trials showing survival benefit. When you do tease a little bit into it, there were some intermediate stage patients that did creep into that study. When you look at the-- Terence had said, the objective response rates in those studies are about 30%, 33%. For us as interventional radiologists, that really doesn't excite us. Because we're used to, historically the TACE is 55%. You can go up as high as, 70%, 80% if you look at some of the Japanese literature where they go sub-selective.

Then with TARE, it can range depending on what stage you treat. For instance, with our study, with the RASER study and the LEGACY, you saw upwards of 90% complete response, not just subjective response, but complete response in the early stage patients. So again, we're not getting super excited about 30%, 33%, but that is something to get excited about, I think, in the medical oncology community.

But if you tease out that a little bit more, and certainly we've seen these fantastic complete responses, miraculous type responses, I would say, in individuals with large tumors, vascular invasion, and then it looks like it almost completely goes away, it's fantastic, but it's only 7%. Offering 7% to our patient population, I don't think anyone gets really excited about that. Hey, listen, you come in, you have advanced stage, you have a 7% chance of having complete response.

I think it's good shot when you look at horrific disease that's infiltrated, taking up the majority of the liver and vascular invasion everywhere, that we know local regional therapy really won't do anything alone, but still, to me, it's not good enough, Yeah, 7%. We got to increase those numbers. When you look at HCC, it arises in the context of chronic liver disease and inflammation. In that type of setting, that creates a background of immune suppression. That's why I think we don't get as high of a response as we want.

When you look at Valerie Chu out of Singapore, she did some basic science research when it came to TARE. She saw that TARE actually upregulated T-cells and a host of cells that, man, I got to go back to medical school to remember, natural killer cells and CD3 positive, CD8 positive, and so on and so on. We saw that this had actually disrupted the tumor microenvironment, and potentially that can be exploited for an immunomodulatory effect, which is a fancy way of saying those checkpoint inhibitors potentially could improve their response rates for individuals with HCC.

For me, I like a radiation-based therapy. To be transparent, there's also data with external beam radiation as well. But obviously, I'm more biased towards Y90, TARE, to immunomodulate checkpoint inhibitors because for me, radiation is indiscriminate. We can modulate, as you were saying before, giving a lower dose, or we can give a higher dose. For me, in the advanced stage, you also look at the subset of patients with vascular invasion in both of those studies, and they didn't do so hot.

But we have studies like DOSISPHERE that show that if even with VP2, VP3 invasion, you target the portal vein on your mapping study, that is our marker for success. If we target it well, you saw a very high median overall survival benefit in that patient cohort. For me, I would like to combine Y90 or TARE with checkpoint inhibitors because I think that will help potentially disrupt the tumor microenvironment and help the checkpoint inhibitor with its effects.

There is basic science that has been published on this, and we've had multiple articles now published showing the safety of combining a checkpoint inhibitor. For me, that could potentially be a more cost-effective way of treating patients because we have a study out of Seoul National University where they combined single-agent Durvalumab with radioembolization in the advanced stage population and showed a significant survival benefit in that study.

For me, the combination of a TKI or a CTLA-4 is really just trying to potentiate the checkpoint inhibitor. Potentially, we can do it, I never thought I would say this, but in a more cost-effective manner with radioembolization as opposed to dual agents. Because all you're trying to do, let's say even with a TKI, that's the argument for TACE as well or any type of embolization, the TKI causes that angiogenesis to constrict and you cause a release of biomarkers. As Terence was saying before, TACE could potentially achieve that as well.

I think ultimately, we're going to try and mix and match, try to find the best way certainly but potentially a cost-effective way of treating these individuals.

[Dr. Tyler Sandow]
I like it. It all comes back to the primer effect like you were highlighting, Ed. It's whatever it takes to get the primer effect for the immunotherapy to work.

[Dr. Terence Gade]
Just to build on that, I think it's such an interesting topic generally when we think about this and both of our local regional therapies, endovascular local regional therapies, well, all of our local regional therapies, but we're focused on endovascular, have been shown to stimulate the immune microenvironment. They're very different therapies than the antivascular therapies we've been talking about.

They both have really profound effects on the microenvironment in terms of what it's doing to the immune compartment itself, how it's modulating the tumor cells themselves and how those are conditioning the microenvironment and how that affects the immune microenvironment and the function of the immune cells. I think we have a lot to learn and really there'll be some exciting data coming out soon, we hope, around this.

But there's a lot to learn about how we think about our therapy specifically and really not just really synergizing our local regional therapies with different immunotherapies. The other aspect of this is I think in the long term, we're not going to be limited to checkpoint inhibitors. We're going to have a lot of other therapies that are modulating other immune compartments, in particular dendritic cells, which I think are going to have maybe even better suited to synergizing with our therapies.

I think it's an exciting time and I think there's a lot of data and a lot of learning to do over the next several years to inform how we can best do this. I think that's the biggest question going forward.

[Dr. Tyler Sandow]
A quick clarification, what were the objective response rates in RASER? I remember them being pretty high, but was it 98% objective response rates or pretty high?

[Dr. Edward Kim]
Yeah.

(5) Who Benefits From Combination Therapy?

[Dr. Tyler Sandow]
Ed Kim knocks them down with radiation. That's the one thing we were able to take away from that. Now, let's say I have a patient with HCC. When do you look at a patient with HCC and say, this is somebody that would benefit from combination therapy, be it local, regional and immunotherapy?

[Dr. Edward Kim]
I would say as a simple straightforward answer, most advanced stage population, if they're eligible for local-regional therapy, they will also get systemic therapy, usually in the form of a checkpoint inhibitor, either atezo-bev or Durva/Tremi. That's the simple answer. I would say that in the intermediate stage, now, for multifocal bilobar disease, that is enumerable, we tend to either go straight to systemic or treat one side of the lobe, usually with the most disease, with TARE.

The TARE's purpose in that situation isn't to elicit an objective response per se to that lobe, but is theoretically as an immunomodulatory effect for the systemic therapy. Now, this has yet to be proved, but there are signals from various studies that show that there is a potential benefit in that type of situation. Just recently, in the American Journal of Gastroenterology, Yo et al. looked at meta-analysis of individuals with HCC who received immunotherapy versus those who received the combination of immunotherapy and TARE and showed a survival benefit in that patient population with the combination of 19.8 months versus 9.5 months for all comers.

Again, it hasn't been in print yet, but it was just released in September. This is more and more evidence coming out that the potential synergy of TARE and immunotherapy could be beneficial for patients.

[Dr. Tyler Sandow]
What about you, Terence?

[Dr. Terence Gade]
Yeah, it's really a decision, I think, that needs, for us, is made in concert with our oncology and hepatology colleagues about, when a patient, as Ed said, has reached a point where they become candidates for systemic therapy and how we think about layering in a local regional therapy for that. In the context of really bulky disease, I think there's a real benefit there. I think what we know about checkpoint inhibition and modulation of the endogenous immune response in general is that it does better with a smaller disease burden, especially in some of these patients who have really large burden disease.

In those contexts, we've seen a lot of enthusiasm from our colleagues about layering in local regional therapy. I think, like Ed said, in the absence of evidence, it's a difficult question to answer, especially because, in the real world, we're seeing, like Ed said, patients getting both of these therapies, but it's hard to interpret data so far because the scheduling is not consistent across patients.

I think that is going to be one of the most important questions for us, is how to layer that in. There's data coming out of MGH about how checkpoint inhibitors are normalizing the vasculature. As we think about our therapies, which are, endovascular, it may be that having a checkpoint inhibitor on board prior to our therapies not only can help with priming the immune system, or modulating the immune system, but also enhancing our ability to deliver our therapies. I think we have a lot to learn about that scheduling and trying to interpret the data when we have this variation makes it a little bit more complicated.

(6) The Role of Adjuvant Immunotherapy in Early-Stage HCC

[Dr. Tyler Sandow]
I want to ask you a question to follow that because you talked about modulating the treatment response. What about, do you ever see a role for immunotherapy even in the early-stage patient, not necessarily as the primary treatment, but maybe as a adjuvant treatment after a favorable response? Whether it be resection, ablation, Y90, TACE, anything, in an early-stage patient, do you ever see a role for immunotherapy there?

[Dr. Edward Kim]
Yeah. It hasn't been published yet from a peer-reviewed process, but the IMbrave050 has been making the rounds in resectable patients and ablatable patients with high-risk features. Now, it's debatable in terms of this study of what the high-risk features are because they included ablation for lesions up to 5 cm in size, although the median size was much smaller. It was a positive study, again, not peer-reviewed, but I think we can certainly draw some inspiration from this study where we do have individuals who are, by the strict letter of the law, high risk.

Maybe they're larger tumors with high AFPs in the thousands. On explant, there's a microvascular invasion, or there's maybe an infiltrative appearance, et cetera. These types of individuals certainly could benefit from an adjuvant therapy of a checkpoint inhibitor. This can include ablation, and certainly Y90, RADseq, can expand, again, within LEGACY study of a solitary HCC up to 8 cm in size. Those patients who achieve a complete response, but, again, have high-risk features, let's say high alpha-fetoprotein, infiltrative appearance, could potentially benefit from an adjuvant therapy.

Now, what is the goal of that adjuvant therapy is another question. If these patients are transplant-eligible, and it's a controversial issue, but here at Sinai, we will use checkpoint inhibitors to sometimes bridge patients to transplant. But I know that there are some institutions that are quite cautious of doing that, or you can just use it as a curative intent with the definitive treatment being either resection or a locoregional therapy, and then providing that adjuvant therapy to prevent disease from progressing. These are, again, a new world we're living in with these checkpoint inhibitors.

[Dr. Terence Gade]
To build on that, I think, the data that came out of Hopkins a couple years ago, where they combined neoadjuvant CABO and NEVO to really convert locally advanced HCC into resectable disease, underscores, I think, the role for these therapies in that earlier stage disease. The question of, as we start to layer those therapies in with locoregional therapies, what can those outcomes look like, I think we can even, we can build on that. I think that there's opportunity to really change outcomes for that patient population.

(7) Safety of Systemic Therapies in HCC

[Dr. Tyler Sandow]
This is something I was going to ask, Ed, you alluded to it. You said that y'all are even doing adjuvant immuno for some of these bridge-to-transplant patients. I think the question that we all have, and this, certainly, we do a lot of combination treatments as well, but one of the early questions was, is it safe, right? Combination therapy, adding immuno to a locoregional therapy, is it safe for patients? Can you speak to that a little bit?

[Dr. Edward Kim]
Yeah. We have several studies that have been published, one out of Ryan Hickey's group in NYU that showed about 30 patients with TARE and a PD-1 inhibitor that was shown to be safe, very few Grade 3, 4 toxicities. We also published our experience here at Sinai, about 20 patients, TACE, 20 patients with TARE that also had PD-1 inhibitor that showed it to be safe. Pierce Chow out of Singapore published a Phase 2 study that combined TARE and PD-1. Again, showed it to be very safe. I already cited the Seoul National data with Durva and TARE, that again showed it to be quite safe. We're having a bunch of studies that should read out soon. LEAP-012 should be reading out, as well as EMERALD-1. Those are all studies where combination with TACE and checkpoint inhibitors. We'll see how those read out, but if I were a betting man, I would say that for sure it will show that it's safe.

[Dr. Tyler Sandow]
Terence, what are your thoughts? Do you feel that it's safe as well?

[Dr. Terence Gade]
I think it's safe as well. there are recent consensus statements out of the European Society of Organ Transplantation, which underscore that as well. I think that came out maybe this month. So I think it is safe. I think we're going to continue to get more data around that. Our institution was, I'd say, very cautious about it. As we've moved forward, the data is bearing it out as well.

[Dr. Tyler Sandow]
Let's say I'm doing some combination treatments, is there anything I should be watching out for? First off, let's say I have a patient that they want to try atezo-bev. Is there anything that you would recommend from a treatment perspective? I'm leading a little bit, but is there anything that you would recommend on treatment for these kind of patients? How would you time it? Would you have them hold the bev from a certain point? Anything like that?

[Dr. Edward Kim]
It's an interesting question that you ask about the bev because from an interventional radiology perspective, our experience with bev has usually been in metastatic disease. In metastatic disease, we're getting these patients very differently than we are from HCC. With metastatic disease, we're usually getting them in a salvage setting for locoregional therapies. They've usually tried a first, maybe even a second-line therapy that will probably include Avastin or their own maintenance Avastin. The purpose of Avastin is to disrupt the arteries.

We know this, surgeons know this because the arteries fall apart, but that's what Avastin is supposed to do. When we get these patients who've been on Avastin for months, and they come, and the Avastin has already worked, it's sometimes a nightmare going into these vessels to do our microcatheter and wire work. It can lead to dissections and other complications. I think in the HCC setting, it really depends how long they've been on atezo-bev. If you're in a place where it's coordinated care, and from the get-go, you're providing a transarterial-based therapy in conjunction with atezo-bev within a short period of time, probably is not an issue with the bev component. I think it's a different story if a patient has been on atezo-bev for, let's say, several months, and now you get the patient for a transarterial therapy. Now I think that you need to have a little bit more caution when going into that artery.

[Dr. Terence Gade]
That's been our experience as well. I think we've been fortunate in the sense that with coordinated care, we've been able to schedule the interventions typically before patients have started to get some of those therapies. We tend to be first. But yeah, in those patients who had been on it or continue to be on it in the context of our therapies, we've had conversations about holding it for our procedures.

[Dr. Tyler Sandow]
I think that was a great point. I never quite thought about explaining it that way, but you're dead on it Ed, saying that these guys haven't been on it for a very long period of time. As long as we get our treatment at a somewhat reasonable timeframe, we don't really see the long-term effects. That's a great point. I never actually thought about it that way, but certainly something for me to change in our practice as well because routinely, we were inclined to hold bev if we were going to go down that route.

[Dr. Terence Gade]
There is the possibility, just to add on it, to build on that, metronomic dosing of bev has been shown to normalize vasculature. There is also this possibility that you are, early on at least, maybe seeing some improvement in the vasculature if you catch it early enough. The data is, people are still looking at that, but there may be a benefit early on for some of our therapies.

[Dr. Edward Kim]
For our listeners out there, you can also see it as an opportunity to engage with your medical oncologist to teach them about what you do and the importance, if locoregional therapy, especially a transarterial-based therapy is going to be in play, why it's important to send the patient to you a little bit earlier if they're thinking about it because I guarantee you, your medical oncologist has no idea of what you do and the effects of all of that. They just know from a cerebral standpoint, okay, bev may cause some problems for my interventional radiologist, but if you engage with them and explain to them exactly what you do, they may decide, okay, you know what? I may not use the bev. I may go more towards a TACE or Y90 first.

Then maybe hold that for afterwards because it may jail out access for my interventional radiologist. I see it as an opportunity for interventional radiologists to engage with conversations with our medical oncologists.

[Dr. Tyler Sandow]
Well spoken. Love it. Now, what about durva-treme? Does anything make you nervous from that regard? I thought that you sometimes see some bumps in LFTs, from patients that get durva-treme, but it tends to be mild. I'm all about it. Look, I love durva-treme. We use it quite a bit.

[Dr. Edward Kim]
Talking to medical oncologists, I have heard that there is some trepidation when it comes to the CTLA-4. Now, it's usually, with the STRIDE regimen is, from my understanding, a one-time dose of the CTLA-4, the tremelimumab, to prime the system. So far, again, our patients have tolerated durva-treme quite well in conjunction with our locoregional therapy, usually TARE, but there is some concern about the CTLA-4 component because of the toxicity.

[Dr. Terence Gade]
Yeah, we've seen the same. It hasn't really impacted our practice in the context of TACE, but it's something we talk about with our colleagues and something we monitor. It hasn't been something in my experience that's limited its application.

(8) Approaches to TACE & Multifocal Disease

[Dr. Tyler Sandow]
All right. We're getting close to the end. I'm going to wrap up shortly, but I want to do a quick game time thing. I feel like it's a perfect opportunity to ask you guys to learn from the best of the best. Terence, I'm going to lead off with you. We'll call it TACE with Terence. Would you favor cTACE or DEB-TACE? Why choose one over the other? How do you do it?

[Dr. Terence Gade]
I tend to favor cTACE for a couple of reasons. Number one, we do have some concern with toxicity with DEB-TACE, and that can be tumor-dependent. Some of the data that Michael Solon has been generating through some of his NET trials underscore that concern. I've done both, but my preference would be cTACE for that reason. We're focused on being super selective. I think the trade-off, the balancing act here is delivering drug in a delivery vehicle like Lipiodol, but making sure that you're following that up with a sufficient amount of embolic.

I think that if we look at the data, it is the embolic effect that is most therapeutic. There's a lot of interesting considerations when we think about the drugs we're using and how they may or may not be working. There is some data out there that again, these molecular subtypes are different in the way they respond to drug and to the embolic effect. I think that consideration does factor in for us, p53 mutants versus beta-catenin mutants will respond differently to TACE. I think drug can play a different role in those contexts. In my mind, I'm thinking a lot about how am I going to deliver the drug, but also make sure that I can deliver embolic so that I can take advantage of the ischemic effect.

I think that Karen Brown's trial in JCO in 2016 is really the only randomized control data we have that really informs the relative roles of those two phenomena inside of toxicity.

I think that I'm keeping that in the back of my mind, and I'm focusing on making sure I have a satisfactory embolic effect. I think again, the challenges we come up against are endpoints and how do we determine what the endpoint for the procedure is. I think that's dealer's choice. I'm still looking at stasis, but I am using cone beam more and more to understand what the distribution of my embolization looks like and to inform, are there integrating software platforms that can inform on feeding vessels that I may not be recognizing and integrating that into the data I'm getting from the staining, has been really helpful in ensuring that I'm targeting all the vessels that need to be targeted.

[Dr. Tyler Sandow]
Now since you're a cTACE a guy, are you a dox-only or are you a triple-drug guy? How do you like to do cTACE?

[Dr. Terence Gade]
I'm a conventional kind of guy. I still favor the triple-drug regimen. Based on some of the data from our lab, I don't think any of those drugs are particularly well-suited to HCC. We know from the 1988 trial that dox, in and of itself, is barely better than nothing at all for the treatment of HCC, at least systemically. I think if you're going to treat with drug, you want to think about the drugs we have getting as much of a variety of targeting drugs onboard. I think the only drug we have data for that actually demonstrates potentiation by ischemia is mitomycin.

That's why, particularly if I had to choose one, that's the drug I'm choosing because I know obviously this has been informed by drug availability and shortages. In different timeframes we haven't had our choice of drugs, but if I'm choosing one drug, it's going to be mitomycin. But I think there is a huge opportunity, and I will shamelessly plug some trials we have going on here at Penn that are thinking about a little more rationally designed TACE cocktail. We might get a little bit far afield here, but I think we might start to think about TACE and locoregional therapy, in general, a little bit differently.

Not just as a cytotoxic therapy, but how does it condition the microenvironment? If we're conditioning the microenvironment, we can think about how we can create dependencies through that conditioning. Then by identifying those dependencies, we can target them. You're seeing a lot more metabolic therapies come out. As we learned a lot more about tumor metabolism, we see clinical trials with single-agent metabolic inhibitors where they're combining that with dietary interventions. You're creating dependencies by altering a patient's diet based on the tumor type.

That's always amazes me because we can change the diet of the tumor very, very quickly with our therapies. We don't have to put the patient on a diet, we can change what the tumor is eating. Thinking about that in context of some of the new drugs is a really exciting opportunity. I know that's not directly on point, but I couldn't help myself.

[Dr. Tyler Sandow]
Incredibly interesting. I feel like talking to two of the best of the best, that's where we're going to get to hear all the cutting-edge techniques. Now it's my turn to abuse Ed. I'm going to call this Dosimetry with Ed. First off, I think I want to ask you the tough question first. I think, to me, multifocal HCC can be one of the most challenging from a RADseq or from an ablative Y-90 perspective to treat. I want to ask you, how do you treat multifocal HCC? Ed, take it as far as you want to take it.

[Dr. Edward Kim]
Oh, number one, I'll agree with you 100% on that, Tyler. I think multifocal, bilobar disease is the most difficult to treat with radioembolization. I don't think we've figured it out. As you said, you had mentioned ablative dose. The ablative doses are really, in my opinion, there are surgical principles. We've taken a page out of the playbook of our surgeons. When we do ablative type doses, it's either in the setting of a RADseq, where we sub-Couinaud segment, and we're giving doses.

If you follow the LEGACY study, based on observational study, the threshold seems to be 400 grey on a subset analysis that was performed and published in the European Journal of Nuclear Medicine that showed a complete pathologic necrosis rate. While it was complete response as well according to modified resist, but a complete pathologic necrosis rate when that 400 grey threshold was observed. Again, not a prospective study where there was dose escalation done to see what the optimal dose threshold is, but an observation of 400 grey and above.

The RASER study as well also observed very high doses, absorbed tumor doses on post Y-90 PET of 1,000 grey. I'm putting this into context of ablative dosimetry in Couinaud segments. Usually less than a Couinaud, but the definition that was originally made is two or fewer Couinaud segments. Again, a surgical anatomic resection. Another ablative type of concept is with portal vein invasion where we're blasting away, Etienne Garin published in DOSISPHERE, where the dose threshold that he saw was 205 grey, where he saw a survival advantage in those individuals and higher objective response rates and median size of, I believe it was about 7 cm.

Not small tumors but larger tumors. Again, really blasting away at that like a surgical principle. The other one where we blast away is radiation lobectomy potentially for purposes of hypertrophy of the future liver remnant, but also treating the tumor at the same time and observing tumor biology. If the patient truly is a potential surgical candidate, their Child-Pugh A, they have very good underlying liver function, they should be able to take that hit to one lobe and hypertrophy the other lobe. Now, going back to your original question, multifocal disease, when we talk about those ablative settings, again, the portal vascular invasion, the RADseq, the radiation lobectomy, in my mind, since you're a sports guy, I'm thinking of offense.

We're thinking the best defense is a great offense. What drives me nuts about multifocal disease is now you have to start thinking about defense because you don't want to harm the background liver. Unless the patient has a high tumor-to-normal ratio, we're talking four or five to one where you know that you're going to get majority of your dose to the tumor and you have to take into consideration potentially the number of particle-specific activity. You really have to try and calculate how much is the background liver going to get from the dose that you're giving.

That becomes very difficult. If it's multifocal unilobar, I'll do a radiation lobectomy for that, cross my fingers, and hope that there's no progression in the contralateral lobe. If it's bilobar, the way that I practice right now, and Terence might like this a little bit, is I'll do TARE to the side with the most disease burden and then try and pick off the other side with TACE. Now, the other alternative is, as I said earlier in this podcast, is to do TARE to the side, the most disease in an intermediate-stage patient, and then simultaneously put them on a systemic therapy, usually a checkpoint inhibitor, in combination with something else, either a CTLA-4 or bevacizumab.

Again, cross our fingers and if they progress through that, then try and revert to TACE for that contralateral lobe. I agree with you, dosing for that multifocal disease is hard because we're trying to keep the dose to the background liver somewhere below about 50 grey because background liver damage can then occur. If you're, for instance, Marnix Lam out of the Netherlands, there's a great predictive modeling for really dosing for that and sparing the background liver.

(9) Treating Large Central HCC Tumors

[Dr. Tyler Sandow]
I love it. What I'm going to take away from this is I heard particle count and sphere activity. That's basically my love language when it comes to Y-90, something that I truly will nerd out and geek out on. I actually gave a talk on that, and you asked me a very good question that I now want to flip and ask you, I'm going to get you back. How do you treat a large central tumor? There are some techniques, and thinking about this, I think there are certain techniques that you were probably trying to elicit out of me whenever you ask me that question. I think there are certain critical techniques that it comes to when you're treating a large central tumor. How do you go about treating a large central tumor that you might be able to get an ablative dose in? What are your considerations and how do you do it?

[Dr. Edward Kim]
Usually, if you have enough experience, whether you do TACE or TARE when you see these central tumors, immediately, depending on your mindset, you might be like, "Oh,yeah, I'm super excited for this," or you might roll your eyes and say, "Okay, it's going to require a lot of work." So usually, it's small feeding vessels that come off approximately from your main vessels that go to either Segment 5, 6, 7, or 8. The goal is to, number one, protect the non-tumoral parenchyma, which will be distal, but also to drive your therapy into the tumor-feeding vessels.

Now, either of these vessels are innumerable, or they're too small for even a, let's say 1.7 French microcatheter to navigate into, or if you want to, you might be there all day navigating into like seven different feeding vessels. I found that the more elegant way of doing this is to either put in a 6-French guide, and then simultaneously put a microcatheter with an occlusion balloon in the distal segment, occlude that protect dry flow proximally, and then inject your therapy just proximal to that balloon. It should go with the flow into the tumor-feeding vessels because now there's not a competing flow of the normal parenchyma. You can do this, we've done this both with TARE, with glass microspheres and also with conventional TACE. It has been described by both-- Beau Toskich described it. I don't like the term that he uses, but he calls it the predator technique. Then the Japanese have also described it with TACE flow diversion technique.

[Dr. Tyler Sandow]
You're talking about doing tandem microcatheters through that 6-French guide catheter, correct?

[Dr. Edward Kim]
Correct.

[Dr. Tyler Sandow]
I assume you're using a sniper or maybe a neuro catheter, a scepter, or something like that?

[Dr. Edward Kim]
Yeah, both of those are I think, acceptable.

[Dr. Tyler Sandow]
Perfect. Incredible. See, this is perfect opportunity for me to just geek out and be a fan of the best of the best. All right. When do you re-image patients? Patients that are these multifocal intermediate advanced patients, when do y'all like to re-image, and when do you make decisions on re-treatment? What makes you make a decision on re-treatment? Terence, do you want to take a lead?

[Dr. Terence Gade]
Sure. Obviously depending on the therapy we utilized for TACE, we're imaging four to six weeks after the treatment. Then for TARE, we tend to image around three months after the treatment. We're trying to be as aggressive as possible. There's clear data that repeat intervention is not only safe but effective. We are limited in our biomarkers, and that's something that's a big challenge for interventionalists, generally. The imaging biomarkers we have are not really designed to assess our therapies, but when we do have clear evidence of residual disease burden, we're trying to be proactive and re-intervene when we think there's a target. That can be as early as that first follow-up. We're not generally waiting very long if we see definitive evidence of residual disease.

[Dr. Edward Kim]
I would say we're a little bit different in the sense that even with TARE, we're following up at six weeks. Now, in the early stage in the RASER, we showed that there was an objective response with high doses at four weeks time. The reason we follow up at six weeks is that we see them in the office and draw labs. If they're an alpha-fetoprotein-producing patient and it drops, but we don't see really any imaging change at that point, we're okay with that because we predict that there's going to be imaging changes that follow with that radiation therapy.

Bulky disease, multifocal disease, larger HCC, those imaging changes may not be evidence until that three-month mark that Terence had talked about. The reason we also bring them in at six weeks and also get imaging is we want to make sure that there is not progression in the untreated areas because, for us, three months is too long to catch something if it is progressing at a rapid rate. We've caught some of these patients where we treated, let's say Segment 5 lesion, and then they had multifocal disease at that six-week interval. That's the time, if it's an early-stage patient, to then institute systemic therapy right away and hope that the patient is going to respond.

The majority of the time you'll see there is no progression. That'll be a good sign, obviously, of the tumor biology. We do want to catch those individuals who have an aggressive tumor biology that could potentially explode a tumor in their liver. We have treated those patients with systemic therapy with checkpoint inhibitors, and we've had a few of them that have responded to that. For us, that's a phew kind of moment because it really made a difference in that patient's outcome.

[Dr. Tyler Sandow]
That's awesome. I could probably stay on here for another three hours and keep asking you guys question after question after question because this is a dream to be able to challenge you guys with some of the tough questions in the world of interventional oncology for HCC, but I think the podcast people are going to kill me if I keep this going forever. I want to try to wrap it up, but is there anything that you guys think I've missed? Is there any future? Where do you think we're headed in the future in the realm of immunotherapy and IO and interventional oncology? What would you guys finish us up with? Feel free to say that I covered it all and it was absolutely amazing. That's okay too. Do you see us playing a big role in other cancers?

(10) The Future of HCC Management & Interventional Oncology

[Dr. Terence Gade]
I'll start with the first question. Where is this headed and what does the future look like? I think that there are several trials that are underway that are going to really inform the role of locoregional therapy in combination with immunotherapy. I think we're really just at the very beginning. We don't have very much data at all. We're practicing blind in many ways. I think the systemic therapy trials, HIMALAYA, IMbrave, have really demonstrated to me, as well as LAUNCH and TACTICS have demonstrated the power of combination therapy.

I think there's a lot to learn about what those combination therapies are and how to optimize them for the most therapeutic benefit. I think that we do need, at some point, to start thinking about better biomarkers that inform our therapies. I think molecular subtyping is going to be the future. We know that's a really, really big focus for oncologists at this point in terms of the trials that are going to be coming out and the postdoc analysis of these studies in terms of how they understand how to apply these therapies. Everybody is focused on the fact that there's only been those low levels of responses in total, the total number of patients.

What does that mean? How do we start to understand who those bad actors are, and how do we think about other therapies for those? I think that's a huge opportunity for IR. I think the other aspect for us is going to be about better imaging biomarkers and how we develop more functional imaging strategies that can inform our therapies, not just necessarily that we need to treat again, but how do we use biomarkers to decide what to treat with? I want to just emphasize that I think that we have a very unique role to play and we have multiple therapies we can offer patients.

I think that the more we play to that strength, the more we think about how we find the right therapy for the right patient, the bigger role we're going to play, and especially in the precision medicine era, I think we have a real opportunity. I think, just in answer to your second question, this paradigm plays out well across a variety of different cancers. We continue to see the growth of locoregional therapy across the oncologic spectrum, but it's going to take this same kind of information to really solidify our role. I think we really need to be part of the studies that are defining these subtypes and then thinking about how we schedule our therapies because these drugs are going to behave in ways that influence how we apply our strategies.

What I'm really most worried about, honestly, is if we are not thinking about that, that we're going to end up with trials where we've applied a certain schedule to our combination of locoregional with immunotherapy, and we might see negative data. Obviously, that doesn't mean that it won't work. It just means that we may not have applied it judiciously. I don't want to walk past a real opportunity. So I think it really underscores the need to better understand how we think about combining treatments.

[Dr. Edward Kim]
For me, when the first immunotherapy trials were being read out, I think there was a lot of trepidation about turf battles within the HCC space. Certainly, we've seen some of this play out in certain practices, but I think instead of the, let's say systemic therapy versus locoregional therapy mindset, it has actually flipped to the complete opposite. We're seeing this played out in industry with collaborations, with combination trials, with either TACE and checkpoint inhibitors, or TARE and checkpoint inhibitors, or even sometimes ablation and checkpoint inhibitors because we're looking for higher response rates.

I think it's flipped to where we've developed a more cohesive, multidisciplinary mindset. Historically, especially in the HCC space, the alliances that were formed were really between interventional radiology and our transplant colleagues, and our surgeons. Medical oncology really, to be quite honest, didn't have much to offer with sorafenib. Now what we're seeing is even greater reliance and a multidisciplinary aspect to the care of HCC with medical oncology in terms of timing of systemic therapies, et cetera. For instance, it goes both ways where locoregional therapy could be first-line, and then as the patient progresses, either combine further locoregional therapy with systemic or to transition them at an earlier point to systemic therapy, instead of constantly doing locoregional therapy and seeing the function of the liver go down, and then sending them to some systemic therapy.

I think we're quicker to pull the trigger now and say, "Hey, let's give systemic therapy a shot here." The flip as well as I stated earlier, where the patient has just massive disease with vascular invasion everywhere. Systemic therapy, you get that complete response, but then two years later you're getting breakthrough HCC and we're doing RADseqs or ablation for those patients, or maybe even TACE, Terence. I think it's more important than ever in this patient cohort. This can also extend to metastatic disease with a multidisciplinary mindset, a teamwork mindset. Ultimately, who benefits the most are patients.

When patients receive that multidisciplinary care, they're getting aspect of care from everybody instead of a siloed approach where you're just hammering with a screw. I think we are going more and more towards that type of mindset, which is again, best for patient care. I 100% agree with Terence, we have to figure out what is the optimal timing. Do we start checkpoint inhibitors first and then put on the locoregional therapy? Do we start the locoregional therapy first and the checkpoint inhibitor, or what is the timing? Is it a week? Is it two weeks later, or is it simultaneously?

I think these things are nuances that we have not investigated at all yet. It's very different if you're doing a locoregional therapy, and you say, "Yeah, we did a combination therapy," but you started your systemic therapy four or six weeks later. That's really adjuvant therapy. That's not really combination therapy, per se. We started a checkpoint inhibitor six weeks before, and now we're adding locoregional therapy afterwards. That's like neoadjuvant therapy. What is the right timing, I think, is a very important question that we need to answer.

[Dr. Terence Gade]
I think further to that, how we're thinking about our interventions when we know we're going to be layering in these systemic therapies, some of those things that I worry about when I'm doing TACE, is that microenvironment too hypoxic? Is it a space where the immune cells can't function, or when we're doing radioembolization, have we created an environment where we're really ablating those immune cells as well? These are considerations we're going to have to sort out, how we change our therapy in the context of the systemic therapy to optimize it in combination with the scheduling.

[Dr. Tyler Sandow]
I love it. I think the key takeaway is that these are exciting times, and it seems that it only stands to benefit the patients, the IR community, and the patients as a whole, really. At the end of the day, it's all about providing the best, most optimal care for the patient that's in front of us, and so, incredibly exciting times.

Podcast Contributors

Dr. Tyler Sandow

Dr. Tyler Sandow is an interventional radiologist with Ochsner Health in New Orleans, Louisiana.

Dr. Edward Kim

Dr. Edward Kim is the director of interventional oncology and a professor of radiology and surgery in the division of vascular and interventional radiology at the Mount Sinai Medical Center in New York City.

Dr. Terence Gade

Dr. Terence Gade is a practicing interventional radiologist with at the University of Pennsylvania.

Cite This Podcast

BackTable, LLC (Producer). (2024, January 8). Ep. 402 – Immunotherapy in HCC: Evolving Treatment Paradigms [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.