Current Practices In Combination Therapy for Hepatocellular Carcinoma

[Dr. Tyler Sandow]
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…

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…

…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]
…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'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. 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.

[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. 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 an opportunity to really change outcomes for that patient population.