Dr. Harding:
Welcome to First-Line HCC in Focus: Survival, Safety and Real-World Evidence, an ASCO Post Roundtable. I'm Dr. James Harding from Memorial Sloan Kettering Cancer Center and joining me today are two of my dear colleagues, Drs. Anthony El-Khoueiry and Drs. Katie Kelley. If you can, please introduce yourselves.
Dr. Kelley:
Hello, I'm Katie Kelley. I'm a GI medical oncologist focusing on hepatobiliary cancers and clinical research at the University of California, San Francisco. Thanks so much for having me, Jim.
Dr. El-Khoueiry:
Hi, my name is Anthony El-Khoueiry. I'm a GI medical oncologist at the University of Southern California in Los Angeles, also focusing on hepatobiliary cancers and phase one drug development.
Dr. Harding:
Thank you. I'm really excited to join you today to talk about updates from the ASCO 2026 meeting. I think right now we'll move right to our first segment where we'll discuss a case of intermediate-stage liver-limited HCC. So we'll get right to the case. This is a 64-year-old woman with a past medical history of diabetes type 2 and longstanding hypertension. On an annual physical exam, she was found to have an elevated liver function test, and elevated AST and ALT. And this prompted a protected medical workup, which included an ultrasound of the liver demonstrating a mass in the right side of the liver. This prompted an MRI of the liver and additional testing, which ultimately showed diffuse steatosis, a segment 8 mass that measured about 8 by 6 cm. There also appeared to be a satellite or separate lesion of about 2 cm within that segment.
And then there was a question of perhaps some right hepatic vein invasion, although that was not clear. Child-Pugh was A5, ECOG performance status 0, AFP 500, and a biopsy was completed that demonstrated well to moderately differentiated HCC. And if we look to the next slide, you can see a representative image of this case. And I guess what I'd like to do right now is pick the brains of these experts in the field as to when you see a case like this in your clinic, what are the next steps? What would you do now? And maybe we can start with Dr. Kelley.
Dr. Kelley:
I think this is an interesting case that's representative of a lot of patients we're seeing these days, where the person probably, it sounds like, didn't have any known history of liver disease. I see you nodding there, Jim.
Dr. Harding:
Yeah.
Dr. Kelley:
But clearly risk factors for metabolic associated steatotic liver disease (MASLD), with the longstanding diabetes particularly being a strong risk factor. And then I see on the MRI that the patient had diffuse steatosis or fatty liver changes. So while the odds ratios are low, we do know that steatosis and MASLD increase the risk for HCC over time. And that's the risk factor for their HCC in this case. So I guess where I'm getting at with that line of questioning is, how healthy is their underlying liver in terms of what options do we offer them? Because if there's a lot of fibrosis and cirrhosis, then they will not be able to tolerate more extensive local regional therapy than if the liver is very healthy. So I guess I'll ask, did the biopsy at all include any background liver?
Dr. Harding:
Yeah, the biopsy did include background liver. Really, it was just steatosis. I mean, the patient had otherwise clinically completely intact liver function, normal platelets, no evidence of portal hypertension. So when we evaluated this case, obviously this was a really keen for multidisciplinary review and I think many options were considered on the table.
Dr. Kelley:
I think at our tumor board, we would probably start with local regional therapy in this case. Whether or not the hepatic vein is involved is a key question in terms of would she would ever be a transplant candidate at 64 years old; the vascular and macro vessel invasion of hepatic vein would be a contraindication. But we would start with local regional therapy in this case with preserved liver function and a primary lesion, satellite lesion, and possible limited vascular invasion. We'd probably start with Y-90.
Dr. Harding:
And Dr. El-Khoueiry, what are your thoughts on this case? Would you guys proceed similarly?
Dr. El-Khoueiry:
Definitely a multidisciplinary discussion and definitely liver-directed therapy would be very high or priority as far as treatment approach. I do want to just emphasize though that this patient has a couple of high-risk features that worry me a bit. The AFP is at 500. There's more than one lesion, even though it's a satellite in the same segment. So that adds a bit to the risk of the patient. Always in multidisciplinary discussion, we start with the end in mind. So what are we trying to achieve? Is this a patient that we could potentially treat and downstage to get to a curative treatment? So, this is a patient, again, with two lesions, the questionable hepatic vein involvement. So, let's assume there is no hepatic vein involvement. If there is a great response, can we get this patient to a point where they can have either a resection or a liver transplant? I agree also as far as in the U.S., the practice would most commonly gravitate towards Y-90 transarterial radioembolization. Of course, we have evolving data on concurrent liver-directed plus systemic therapy, and we can maybe talk about that next, but I'll stop here.
Dr. Harding:
Well, this case was presented in a multidisciplinary review given the intact liver function, but given the evidence of a higher risk disease, the decision was indeed made to proceed with a locoregional therapy with the hope of downstaging. The thought was the potential for even resection given the health of the liver, but transplant was also considered as a potential option in the future. And we did proceed with local regional therapy. In this case, we did a radioembolization which was tolerated well, and we'll talk about that in the next segment. But to the point, we recently at ASCO 2026 saw two interesting presentations about the utilization of chemoembolization with or without immunotherapeutic combinations. So as we know in the advanced metastatic stage, there are several options for combined immunotherapy that improve survival over tyrosine kinase inhibitors, but the question has been, can we move this to an intermediate-stage disease? And so with that in mind, I guess Dr. Kelley, one of the abstracts that was presented was EMERALD-3. I know you were chairing that session. I wonder if you might comment on EMERALD-3 and your thoughts related to it?
Dr. Kelley:
Yeah, this is a very interesting area, and there's not an absolute right or wrong answer here. But we also had good fortune to be part of an education session on the topic of when do we combine systemic therapy with local regional therapy and intermediate-stage BCLC-B HCC just like this case? Well, this case is technically a C depending on it all hinges on that vascular invasion question, but this person is straddling the B/C domain for sure. So, I think the key points are that it's our endpoints and goals as Dr. El-Khoueiry mentioned earlier. And we know from multiple studies now, EMERALD-3 most recently that combining systemic therapy, immunotherapy combination with TACE, and we don't know yet for Y-90, but we can presume it may be similar, will prolong progression-free survival. The question is, what is progression-free survival to a patient and in their long-term journey?
If it doesn't correlate with overall survival, we have to ask our question of, is it better for the patient to do all of this upfront together to prolong this interval of time, or is it better to do things sequentially and space out toxicity, et cetera, because we may end up with the same overall survival at the end of the day and potentially less toxicity without doing all things at once. And the data right now do show substantially higher toxicity from EMERALD-3, the serious adverse events rate, for example, in the triplet combination of durvalumab, tremelimumab, and lenvatinib, which were given in arm A of that study, the primary comparison arm, that arm, which improved progression-free survival, also increased serious adverse event rate to 64% with the triplet systemic therapy plus TACE.
That's really high because as we all know, serious adverse events are generally hospitalizations and often patients have sequelae. So again, it's not a trivial issue to think about the toxicity. And coming to what Dr. El-Khoueiry mentioned earlier, though sometimes that progression-free survival time point can be particularly valuable in patients who might be eligible for transplant or downstaging later. So if there's a goal in mind that does benefit from just progression-free survival duration prolongation, sometimes this combination I think does make sense with the endpoints, but in the average patient who's not a transplant or surgical candidate, I don't know yet that we have the data to support it.
Dr. Harding:
Dr. El-Khoueiry, your thoughts on this interesting topic.
Dr. El-Khoueiry:
No, I fully agree with Dr. Kelley. I think that the other benefit of the combinatorial approach of TACE plus systemic immunotherapy has been a higher response rate, where again, in patients where we're aiming for downstaging and have high-risk features, sometimes that PFS improvement and response rate improvement become handy and potentially useful in these situations. I do have to agree that globally with just the PFS improvement that we are seeing at this point, doing this in all patients with intermediate-stage HCC, doing the combination approach in all patients would be an overkill at this point. I do want to mention that in EMERALD-3 there was another arm. It's arm B, which is the STRIDE regimen of tremelimumab/durvalumab plus TACE. So this was a secondary comparison, which also showed an improvement in PFS and also an immature OS that looks to favor the combinatorial approach that based on the statistical design, we cannot now officially compare arm B and C with an official statistical significance, but at least the data looks promising for that arm.
And going back to Dr. Kelley's point, it seems that having that arm without lenvatinib, it may have been a bit more favorable in terms of reduced toxicity and maybe allowed for better treatment intensity and allowed patient to stay on therapy. But again, we have to wait for more mature data.
Dr. Harding:
I was personally intrigued and fascinated by that signal, and I think many people were. My impression is as yours is, let's get some extended follow-up. And the discussant, Dr. Chan, I think made a very good point that echoes Dr. Kelley's point, is that seeing quality of life data that was hopefully embedded within these studies I think would be very helpful to us all in determining in part who and when someone should get combined immunotherapy in relation to local regional therapy. And so for this specific case, this occurred really before many of these readouts. And as I stated, the patient was slotted for Y-90. Now I do want to just quickly ask both of you with regard to local regional therapy, obviously I consult my colleagues. Outside of the United States, Y-90 is less frequently done. Can you guys comment from your perspective, why do we choose Y-90, or why has there been an increase utilization of Y-90 in the United States? Dr. Kelley?
Dr. Kelley:
I think it does have very promising local regional response rate data, especially for slightly larger tumors, and it does have penetrance to limited vascular invasion regionally in terms of the Y-90 beta-emitter spectrum of activity. So I think there's the local response rates and also it is generally well tolerated with its adverse event profile sort of spread out over 6 weeks not so concentrated as a TACE where we see more immediate transaminitis and fevers and post-embolization syndromes are a little bit more acute with TACE, whereas Y-90 certainly does have toxicity, it's just it's a little bit more gradual in its distribution. I'd love to hear what Dr. El-Khoueiry says on that topic as well.
Dr. El-Khoueiry:
Yeah, you're not going to hear controversy here, but we are frequently aligned. So no, I agree. But I think I just would add that I think the utilization of Y-90 radioembolization has evolved towards more focused therapy, more towards radiation segmentectomy at most lobectomy, so not treating the entire liver, which previously was associated with higher toxicity. I think that's an important point to keep in mind.
Dr. Harding:
And with this case, this was exactly what happened, a radiation segmentectomy given the focused area of the disease and we'll get to the next component of the case shortly. I think that the available evidence that we talked about I think would suggest as the combinatorial approaches. Are there any ongoing studies, maybe Dr. Kelley, that would be evaluating Y-90 with immunotherapeutics? And what are your thoughts about those?
Dr. Kelley:
I also was intrigued going back to the EMERALD-3 study. I was also very intrigued by arm B, the durvalumab, tremelimumab without an anti-angiogenic, which we all know our anti-angiogenic therapies are very difficult to sustain over more than say 9 months of time. People get proteinuria, people get hypertension, they need to stop for procedural holds, and they have just cumulative toxicity. So arm B does not have an anti-angiogenic therapy, just the durvalumab/tremelimumab. And in fact, to your question, there are several ongoing studies that look at durvalumab/tremelimumab with Y-90, one is called IOSPHERE and one is called ROWAN. And then there's a different study, EMERALD Y90 that looks at Y-90 with durvalumab and bevacizumab. So that one does have an anti-angiogenic and the toxicities I'm concerned about. Those three studies are all phase II nonrandomized because as we've talked about, Y-90 is dominant in the United States, but very limited availability elsewhere.
So, the practicality of doing a randomized international phase III trial really isn't there for Y-90. But those three phase II nonrandomized studies I think will be very interesting to look at how they compare to the contemporary TACE trials, which are very similar patient eligibility. And if we see similar efficacy but lower toxicity or greater efficacy, we can make some assumptions. That'll be the best we can do with a nonrandomized study. But I'm eager to see the durvalumab/tremelimumab trials, ROWAN and IOSPHERE in particular.
Dr. Harding:
Yeah, I think it'll be really fascinating to see how these all play out. I think this was a great session. And so for me, I think the key takeaways are that when we're faced with liver cancer, we really do need a multidisciplinary review. This is a team approach where there are multiple modalities that can indeed cure patients and/or really palliate and control symptoms for an extended period of time. So that's my first key takeaway. I think takeaway number 2 is the liver limited hepatocellular carcinoma, the Barcelona B, it's quite heterogeneous group of diseases with multiple potential approaches. And that's really why we do need to rely on multidisciplinary view and the available evidence. We've talked extensively about TARE in this session, which is involved, is used in the United States with great effect. Likewise, chemoembolization would be considered, I think, a global approach for select liver limited disease.
We're starting to see now immunotherapeutics move into this space and we reviewed several of the resulted studies of combination immunotherapy in this space. I think the key takeaway is we're observing a PFS advantage with immunotherapy and TACE. It is not translated yet to a full overall survival advantage and I think further data are needed before we apply it to all comers. But there is increasing interest in the selective use of this modality in cases. And here you have references to really all of the key prospective data, which I encourage you to read and check the ASCO session from 2026 in this regard. Thank you very much for joining me for this case with my colleagues, Dr. Anthony El-Khoueiry and Dr. Katie Kelley.
