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BackTable / VI / Article
An Introduction to Systemic Therapies for Hepatocellular Carcinoma
Rajat Mohanka • Apr 11, 2024 • 33 hits
Treatment options for hepatocellular carcinoma (HCC) are continuously evolving, and the management of these patients is best approached in a multidisciplinary fashion. Interventional radiologists offer expertise in locoregional therapies such as chemoembolization, radioembolization, and ablation. However, with ongoing clinical trials showing improved patient outcomes through combination therapies—such as locoregional therapy and systemic therapy—it is crucial for interventional radiologists to understand the various systemic therapies available to guide patient management effectively. Interventional radiology plays a critical role in enhancing the efficacy and reach of systemic treatments.
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 systemic therapies used to treat HCC. This article includes excerpts from the BackTable Podcast. The full episode is featured below.
The BackTable Brief
• Established as an initial systemic therapy option following the SHARP and Asia-Pacific trials, Sorafenib provided a critical, albeit modest, survival benefit for advanced HCC patients.
• The CheckMate 040 trial introduced nivolumab, signifying a paradigm shift towards the use of immune checkpoint inhibitors, which harness the body's immune response to target cancer cells.
• Distinguished by their targets, with PD-1 inhibitors focusing on T-cells and PD-L1 inhibitors targeting tumor cells, checkpoint inhibitor therapies prevent immune evasion.
• Specific trials such as CheckMate 459 and CheckMate 040 explored the varying effectiveness of PD-1 and PD-L1 inhibitors and showed differential outcomes in HCC treatment.
• Studies and clinical experiences indicate the safety of combining PD-1 inhibitors with locoregional therapies like TARE and TACE, with minimal severe toxicities reported.
• The use of bevacizumab in the setting of HCC poses challenges due to its impact on artery integrity, necessitating careful planning and timing to minimize complications when used in combination with transarterial treatments.
Table of Contents
(1) The Impact of Immunotherapy on Hepatocellular Carcinoma Treatment
(2) Understanding PD-1 & PD-L1 Checkpoint Inhibitor Dynamics
(3) Evaluating the Safety of Immunotherapy with Locoregional Therapies in HCC
The Impact of Immunotherapy on Hepatocellular Carcinoma Treatment
In the evolving landscape of hepatocellular carcinoma treatment, the integration of immunotherapy has marked a significant milestone, shifting the paradigms of systemic therapy from its nascent stages to a more dynamic and hopeful era. Beginning with sorafenib's pivotal role, highlighted by the SHARP and Asia-Pacific trials, the treatment for advanced HCC witnessed a decade of modest advancements until the advent of nivolumab through the CheckMate 040 study. This breakthrough, alongside further successes with IMbrave150, HIMALAYA, and Lenvatinib trials, underscored the potential of immunotherapy and combination therapies in extending meaningful survival benefits.
[Dr. Tyler Sandow]
…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…
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.
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Understanding PD-1 & PD-L1 Checkpoint Inhibitor Dynamics
Immunotherapies, particularly checkpoint inhibitors, aim to prime the body to attack HCC. PD-1 and PD-L1 inhibitors target key interactions between tumor cells and the immune system. This approach hinges on disrupting the immune evasion tactics employed by tumor cells, specifically the PD-1/PD-L1 axis, to rejuvenate the immune system's ability to recognize and attack cancer cells. While PD-1 inhibitors focus on T-cells, and PD-L1 inhibitors target tumor cells, their efficacy in isolation has been outpaced by the success of combination treatments. Clinical trials have yielded mixed results, with single-agent therapies showing limited effectiveness compared to combination therapies.
[Dr. Tyler Sandow]
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. 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.
Evaluating the Safety of Immunotherapy with Locoregional Therapies in HCC
The integration of immunotherapy with locoregional treatments for hepatocellular carcinoma represents a significant advancement but also raises important questions regarding safety and best practices. Clinical experiences and studies underscore the safety of combining transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) with PD-1 inhibitors, showing minimal severe toxicities. It is important to note that bevacizumab, especially in patients undergoing atezolizumab-bevacizumab therapy, can disrupt the arterial system. Therefore, if patients undergo an endovascular procedure, the interventional radiologist should exercise extra caution with wire and catheter manipulation due to the heightened risk of vascular complications.
This situation presents an opportunity for interventional radiologists to coordinate care with medical oncologists, thereby providing the safest therapies for patients in a timely manner. Dr. Kim anecdotally reports that patients seem to tolerate durvalumab-tremelimumab with TARE well; however, there are potential concerns that CTLA-4 inhibitors, like tremelimumab, may cause hepatotoxicity, highlighting the importance of interdisciplinary communication to optimize patient outcomes.
[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.
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.
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