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Current Practices In Combination Therapy for Hepatocellular Carcinoma
Rajat Mohanka • Updated Apr 11, 2024 • 114 hits
Many studies have shown that combination therapy for hepatocellular carcinoma (HCC) has improved patient outcomes, but currently there is no standardized approach for treatment with these modalities. There are, however, promising studies, such as the TACTICS and LAUNCH trials, that describe the benefits of local-regional therapy with systemic therapy. Additionally, many basic science studies describe that altering the tumor microenvironment with radioembolization could enhance the efficacy of checkpoint inhibitors.
Many advanced-stage HCC patients are eligible for concurrent local-regional and systemic therapy, usually in the form of checkpoint inhibitors. Furthermore, checkpoint inhibitors can be considered adjuvant therapy for early-stage HCC patients who are treated with local regional therapies.
Dr. Edward Kim, an interventional radiologist from Mount Sinai Hospital, and Dr. Terence Gade, an interventional radiologist from the University of Pennsylvania, explain the various combination therapy practice models for specific patient populations. This article includes excerpts from the BackTable Podcast. The full episode is featured below.
The BackTable Brief
• The significance of the IMbrave150 and HIMALAYA trials along with the introduction of lenvatinib emphasized the role of combination therapies and further expanded the arsenal against HCC.
• The synergy between radioembolization and immunotherapy agents, like checkpoint inhibitors, can potentially modulate the tumor microenvironment to improve survival benefit.
• The RASER and LEGACY studies describe promising objective response rates and manageable adverse events of combination therapies.
• Emerging evidence supports transarterial radioembolization’s (TARE) capacity to enhance the effectiveness of systemic immunotherapies, with studies indicating survival benefits from this synergistic approach.
• There is potential for checkpoint inhibitors as adjuvant therapy following successful resection, ablation, or other locoregional treatments in patients with early-stage HCC who have high-risk features.
• Tumor size, high alpha-fetoprotein (AFP) levels, microvascular invasion, and infiltrative tumor appearance are considered when determining eligibility for checkpoint inhibitor adjuvant immunotherapy.
• The combination of cabozantinib and nivolumab in neoadjuvant settings highlight the evolving landscape of HCC treatment in which systemic therapies could play a crucial role even in earlier stages of the disease.
• There is ongoing debate on the safety and efficacy of using adjuvant immunotherapy to bridge patients to transplant.
Table of Contents
(1) The Role of Combination Therapy in Hepatocellular Carcinoma
(2) The Potential Role of TARE in Combination Therapy
(3) Adjuvant Immunotherapy in Early-Stage HCC
The Role of Combination Therapy in Hepatocellular Carcinoma
The IMbrave150 and HIMALAYA trials were pivotal in underscoring the importance of combination therapies for patients with hepatocellular carcinoma. It is essential to tailor care precisely for HCC patients between various local regional therapies and their integration with systemic treatments. Dr. Gade emphasizes the uniqueness of having multiple therapeutic options for a single disease, advocating for a personalized treatment strategy guided by the molecular subtypes of HCC, which demonstrate varied responses to different therapies. This tailored approach is supported by an understanding of tumor biology and the innovative use of technologies to determine the most effective therapy for individual patient profiles. The TACTICS and LAUNCH trials both describe improved clinical outcomes of systemic therapy with chemoembolization. The RASER and LEGACY trials show the efficacy of radioembolization in complete response for early-stage HCC.
Dr. Kim elaborates on the promise of combining radioembolization with immunotherapy, based on the premise that altering the tumor microenvironment with radioembolization could enhance the efficacy of checkpoint inhibitors. This nuanced strategy not only aims to elevate treatment outcomes but also considers the cost-effectiveness and patient-specific responses to create a more refined, impactful clinical pathway for managing HCC.
[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?
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The Potential Role of TARE in Combination Therapy
Most advanced-stage HCC patients are eligible for combination local-regional therapy and systemic therapy, usually in the form of a checkpoint inhibitor such as atezo-bev or Durva/Tremi. Recent studies demonstrate the immunomodulatory potential of TARE, which, despite the need for more concrete evidence, shows promise in enhancing the efficacy of systemic treatments. The Yo et al. recent publication in the American Journal of Gastroenterology suggests a notable survival advantage when combining TARE with immunotherapy, underscoring the evolving landscape of HCC management. Dr. Gade emphasizes the collaborative decision-making process in selecting patients for combination therapy, which seeks to consider the disease burden and the potential benefits of reducing tumor load to enhance immunotherapy efficacy. Further research is needed to establish evidence-based protocols for treatment scheduling between immune system priming and optimizing therapy delivery.
[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.
Adjuvant Immunotherapy in Early-Stage HCC
The IMbrave050 study underscores the potential benefits of checkpoint inhibitors as adjuvant therapy for patients with high-risk features, even after they received local-regional therapy or resection. Patients who might benefit from adjuvant immunotherapy include those with larger tumors or those with high alpha-fetoprotein levels and microvascular invasion. Adjuvant immunotherapy could serve as a bridge to transplant or as part of a curative intent strategy. There are emerging innovative applications of neoadjuvant combinations, such as cabozantinib and nivolumab, that have shown promise in converting locally advanced HCC into resectable disease, signaling a shift towards more aggressive integration of systemic therapies in earlier disease stages to potentially improve long-term outcomes.
[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.
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.