Podcast Transcript: Combination Therapy and Clinical Trials for Advanced HCC: What They Really Mean

(8) Evolving Roles of Combination Therapy & Local-Regional Approaches in HCC

[Dr. Tyler Sandow]
I'm like, I would rather just sit and listen. I want to talk about combination therapy because I feel that we are making massive waves with combination therapy. I think we're seeing incredible outcomes. Part of my approach is, even in the early stage, if a patient has a big tumor, they have multifocal disease, they may not be in the BCLC category, they may not be BCLC-C or that far B. If they're not going to go to transplant and they might benefit from a dual-phase approach, I think combination makes total sense in my opinion assuming the patient can tolerate that.

I wanted to get y'all's take and then I want to loop in Zach on how to tackle this. When do you make the decision on combination? When do you say, "I want to not only just treat with immunotherapy but I might treat with Y90," or Zach, when do you say, "This patient would be great from a local-regional, but immunotherapy might make total sense to boost an outcome?"

[Dr. Zach Berman]
I'll start with data and then we can devolve into what we actually do in real life. The two trials that we know about were LEAP-012 and EMERALD-1, looking at the combination of TACE plus various forms of systemic therapy with immunotherapy and either bevacizumab or immunotherapy and lenvatinib. Both of those trials were technically positive. Their primary endpoints were progression-free survival and we're still waiting on both trials for overall survival.

We'll start there, is that we do have some evidence that at least from a progression-free survival TACE extends onto, although I don't think we've treated one patient off-trial with TACE in immunotherapy. We've resulted to mostly Y90. There are two trials open right now, ROWAN and then EMERALD-Y90, both single-arm phase II trials to hopefully address that. In real life, we're doing mostly Y90 in combination. I think there's a lot of reasons we do that.

The first one is Y90 is just a better therapy than TACE, a little controversial, but I think true. Then also to a second degree, and you said it earlier and I think perked my ears a little bit, is this concept of the tumor microenvironment and can we alter the tumor microenvironment and figure out how we can potentially overcome exhaustion as you said as well. These are all just theoreticals right now.

We're starting to get a better understanding of how can we alter the tumor microenvironment, whether it be with radiation or some sort of ablation and cryoablation or electroporation or other types of intra-arterial therapies or percutaneous therapies like intra-arterial immunotherapies or percutaneous injection of modified herpes viruses. All of this is to say that there's probably going to be in the future a lot more combination with proven known effective therapies like Y90 or TACE. Then also in the future, intra-arterial immunotherapy or percutaneous injection of some sort of immunomodulating factors is how I view it.

[Dr. Tyler Sandow]
What are you guys think?

[Dr. Jon Mizrahi]
No, I think that was great. That's where the data is. I agree that at Ochsner, we're very similar to you guys. Tyler could speak on behalf of us using way more radioembolization than chemoembolization, but we are doing a lot of combination. I would say the folks that we considered in obviously BCLC-C, but in the BCLC-B area are exactly what you alluded to earlier. If we know a patient's really not on a transplant route, then we're much more comfortable introducing immune checkpoint inhibitors earlier on in their disease course.

Then if we see a patient who's gotten a Y90 or two, and you see the disease is outpacing the ability of the local therapies to control it, I think that's when we're also saying, "Hey, this is--" or if it's a giant tumor and maybe they don't have [crosstalk].

[Dr. Lingling Du]
Y90, exactly, may not be strong enough, then we definitely feel very free to add on some systemic therapy.

[Dr. Tyler Sandow]
I want to pause here and say, I think that helps with the collaborative nature of how we all behave. I know that you guys do it in San Diego as well. It's very easy for me to say, "Hey, I've hit this thing with Y90 twice, and it's just progressing outside of my treatment zone. I can keep chasing this and I know that I can keep treating it, but I'm losing the race right now. What makes the most sense in terms of taking care of this patient?"

Then it's having a quick interaction with y'all, "Hey, guys, treated it twice or treated once, and it looks like it's progressing pretty quickly. What do you think about immunotherapy here?" Especially in somebody that has preserved liver function, throw more at it. I like the concept of if they're not going down the transplant route, it makes a lot of sense to combine.

[Dr. Zach Berman]
It's somewhat of a culture change though. Traditionally, it's all local-regional therapies possible, and then you're done with chemotherapy and not get local-regional therapy again. They go on to systemic and then, at least in my clinic, just lost forever.

[Dr. Lingling Du]
Right. Medium over-survival of 10 months with sorafinib.

[Dr. Zach Berman]
Yes. That's how it works. It's a culture change a little bit, even from, at a tumor board level, when you have a discussion, it's, "We're no longer just doing local-regional therapy until they either can't tolerate it or have had too much progression." I don't know what the right answer is. We're all trying to figure it out as we go until we have better data, but it's definitely changing pretty quickly.

[Dr. Adam Burgoyne]
I do think all of these studies are very important though, at the risk of busting the chops of my IR colleagues. You guys have a lot of tools in your toolkit, and instead of just doing these things and seeing what happens, I think it's important that we study these things in a prospective way, because, yes, the scenario that you outline of my Y90, we did it twice, we look like they're progressing, we need to move to systemic therapy. That's an easy conversation for us to have.

If you look at these other studies where you're prospectively committing someone to a combinatorial approach of either TACE plus systemic therapy or TEAR plus systemic therapy, those people are going to be on systemic therapy for a long time. We want to make sure that they're actually deriving an efficacy benefit and that, particularly for LEAP-012, that's using lenvatinib for a prolonged amount of time, which has a lot of toxicity.

We want to make sure we're really doing what's best for the patient in terms of improving an outcome, not just doing something to make ourselves feel better.

[Dr. Tyler Sandow]
100%. Totally great consideration there.

[Dr. Jon Mizrahi]
That's why I 100% agree with you. I think what Zach was saying earlier is that, yes, these are positive studies right now because progressive survival is shown to be beneficial. If these are not improving overall survival, I would say these are negative studies. That's what we care about. We're not making their lives any better by putting them on lenvatinib every day. Immunotherapy, most people tolerate fine, but it doesn't make you feel any better unless we're treating your cancer better.

What we care about is overall survival in those patients. I think the jury is definitely still out. If we're not moving that needle, then I would say this will be not the right approach.

[Dr. Tyler Sandow]
We talked about it more in the BSAP, but what about the Cs, the people that would be candidates for first-line immunotherapy? Do you just look at it as an immunotherapy-only thing? Let's say somebody has portal vein vascular invasion, automatic BCLC-C, but they have preserved liver function, are they only going to get immunotherapy? Would you consider a combination approach with immunotherapy and Y90? What is your thought process to that?

[Dr. Lingling Du]
Usually, Y90 works pretty well for portal vein thrombosis from the tumor. If their performance status is great, liver function can handle it. If it [unintelligible 00:32:55] because there's portal vein thrombosis, knowledgeable Y90, usually I combine both.

[Dr. Adam Burgoyne]
Again, this is a bit of a data gap for us. I think you make a very good point that BCLC-C patients are also a heterogeneous group. I think the Bs are very heterogeneous as they are. There's a big difference between a patient that has a three-centimeter tumor with VP1 invasion versus someone that has peritoneal caking and lungs full of metastases. I think that when we're thinking about combinatorial strategies, there's really maybe two considerations.

Is there something you all can do local-regionally to prime the immune system to stimulate it, to have some synergy with the immunotherapy versus are there things that we can do for just better disease control in the liver because that's really where the disease is?

[Dr. Jon Mizrahi]
I've said this 12 times, but I completely agree. I try to say in those patients, is this patient going to die from their enteropathic disease? If so, then I think doing something local-regionally, if we think it will help them makes sense. Exactly what you described, a small tumor that happens to have portal vein invasion, to me, that's a very good candidate for a combination therapy.

Now, you could take the approach of starting them on systemic and then doing Y90 as a consolidated approach, or if you believe in this priming effect, then doing them at the same time, I think you can make arguments for both of those. I think that's one of the optimal candidates for doing combination therapy.

[Dr. Lingling Du]
I also have patients who say have been getting front-line systemic therapy for a little while, more than three months, and then there's one teeny-bitty new cancer HCC in the liver that a lot of times I don't have great second-line option. What am I going to give them? A TKI second line. I will just use Y90 to zap that new spot out and just keep them on immunotherapy. I have patients who do well.

(9) Optimizing Y90 Integration with Immunotherapy: Safety, Timing, & Dosing

[Dr. Tyler Sandow]
Next question. If you go down the combination route, does it matter when you stage-- I imagine the majority of us are all probably going to do Y90 in the US as a combination for the local-regional approach and combination. Does it matter when you start immunotherapy in relation to the Y90? I think that's a question we get often. We'll hear it from other interventionalists and they'll say, "When do I tell our oncologist, when do I have my discussion with my oncologist about when I should do my Y90 in relation to immunotherapy? Should I do it before? Should I do it after the first dose? Should I do it after they've been on it for a while?"

When's the right time to start Y90 in relation to immunotherapy?

[Dr. Lingling Du]
There are a few studies on the combination systemic plus Y90. All very small, 20 plus patients or so, but different studies designed it a different way. Some give Y90 a week before systemic immunotherapy. Some give Y90 one to two weeks after. From all these small trials, I don't think it matters how you sequence it. I would say definitely not the day after Y90 I'm giving them immunotherapy. The liver enzyme is still high at that time. I think if you space everything out one or two weeks apart, in my experience, it doesn't matter that much. Of course, I don't give bevacizumab before Y90.

[Dr. Adam Burgoyne]
I agree. I don't think we know from a tumor biology perspective what's best. The studies that have been done are very small and weren't really powered to ask that question. I think we can comfortably say it's safe so we all feel comfortable doing that, but as you all know, it can be challenging for us too, to know when to introduce immunotherapy in terms of what are we going to monitor, because there's so much inflammatory response after the tear.

Imaging is not going to be our best surrogate moving forward for months until things declare themselves. That also can be a challenge for us as well post-tear. When do we start immunotherapy, knowing what we're going to monitor for response?

[Dr. Tyler Sandow]
I think another point, too, is-- We looked at our own data and we actually found that there was no difference in outcomes or adverse events with when they started immunotherapy to Y90. I have a dosing-related question for you, Zach, because I imagine you're doing lots of Y90 and I got to get you to talk at this table with these oncology geniuses. Do you dose any differently when you do Y90 in conjunction with combination therapy? Do you have any considerations there? Now, I've heard some approaches, but I want to hear yours.

[Dr. Zach Berman]
Yes, totally. I'll even take a step back. We talked about bevacizumab. Most of my experience before atezo/bev was FOLFOX/bev in colorectal patients. These patients were getting FOLFOX/bev for quite a while before I would do radioembolization and their arteries were affected by it. It was a huge issue. I have not seen that issue in my HCC patients. For all the interventionalists out there, I wouldn't use that as a reason not to consider intra-arterial therapy.

I just don't see the same thing. I think our current protocol is just to skip an infusion before, give us a couple of weeks, and then they can start it almost immediately after the procedure as well, continuing it back. As far as dosing, it always talks about the same thing that we talked about previously is what are your intentions. If they have a solitary tumor that's growing, which is our most common scenario that we've been treating after immunotherapy, I'm talking about ablative therapy.

I want this tumor to be gone completely, the one that's growing. The rest of the tumors inside of the liver presumably are being controlled by the immunotherapy. Then you're just using straight ablative dosing. If they have multifocal progression throughout the entire liver, I don't think addition of local-regional therapy is going to be that helpful. Maybe instead of doing a palliative amount of dosing, we can start to discuss switching systemic therapies at that point.

[Dr. Tyler Sandow]
I have a similar approach to you guys. If you can ablate it, if you can give an ablative dose, I ablative dose. I've also seen these patients that have been on immunotherapy that have-- We talked about this in the dosimetry session where they have disease that's controlled. They're not non-progressing disease but not necessarily responding disease, they seem to be in the state where if you flick them hard enough, they're going to die.

They don't necessarily need a massive ablative dose, but they just need a decent dose to be stimulated to die. We had a couple of guys. We have one guy that was thinking he was headed to hospice. He had controlled disease. We wound up Y90-ing him. He had stable disease. He was non-progressing, but he wasn't loving immuno. It was under control. We Y90'd him. Now he's back to playing music in Mississippi, which I thought was really cool.

I've heard of another approach to when dealing with combination Y90 and immunotherapy is to not necessarily do the same type of ablative dose as you would to basically leave some tumor viable for the immune system to respond. I can tell you I don't personally do that. I would rather just go in and kill it straight up. What are your thoughts on that?

[Dr. Zach Berman]
I don't know if I would necessarily do that just to do it. I understand the complete physiology and reason why you'd want to do it. I think the idea of partial ablation with immunotherapy is very intriguing, and there's some early evidence in melanoma prospectively to show it. I would love to do that as part of a trial.

[Dr. Tyler Sandow]
You wouldn't advocate for someone to do it outside of a trial right now?

[Dr. Zach Berman]
No. I think if they're having growing disease, you have to treat the entirety of the disease, which is just an oncologic principle. Basic oncologic procedures or not, "I'm going to take out two-thirds of the tumor and just leave some behind." I in my opinion, a patient should understand the risks of what they're doing before having that done. A clinical trial is the best way of doing that where there's a very thorough informed consent.