Dr. Harding:
Welcome to First-Line HCC in Focus: Survival, Safety, and Real-World Evidence, an ASCO Post Roundtable. I'm Dr. James Harding, an Associate Attending at Memorial Sloan Kettering Cancer Center. And joining me today are two of my dear colleagues, Drs. Katie Kelley and Dr. Anthony El-Khoueiry. If you please, can you introduce yourself to the audience?
Dr. Kelley:
Hello. Thanks so much for the introduction, Dr. Harding. I'm Katie Kelley. I'm a Professor of Clinical Medicine at University of California, San Francisco, and I focus on hepatobiliary cancers and clinical trials. Thank you.
Dr. El-Khoueiry:
Hi, I'm Anthony El-Khoueiry. Happy to join my dear colleagues this morning. I'm a medical oncologist at the University of Southern California in Los Angeles. I focus on hepatobiliary cancers and phase I drug development.
Dr. Harding:
Great. Thank you so much for joining us. We're recording this right after the 2026 ASCO Annual Meeting, and I'm actually looking forward to discussing the clinical implications of some of the data presented.
Our first segment, we discussed a patient with localized liver cancer. So, I'll move now to the case so far. We just presented a 64-year-old woman with a liver-limited HCC and a history of type 2 diabetes, hypertension, and fatty liver disease. An ultrasound demonstrated a right liver mass. MRI in full staging demonstrated a segment 8 mass measuring 8 cm in maximal dimension, and a potential satellite in segment 8 above 2 cm. There was a question of a right hepatic vein invasion but not clearly documented. The patient had excellent ECOG performance status, Child-Pugh A liver function, and elevated AFP. The patient received local regional therapy with TARE, which was an attempt to downstage either for surgery or potential transplant. This was well-tolerated.
Unfortunately, at the follow-up restaging scan, this patient developed multiple pulmonary metastasis in the residual part of the liver segment, the left side of the liver, multiple small lesions consistent with HCC. We also saw some advancement of disease into the portal vein. AFP unfortunately increased from about 500 to 3,000. The patient was completely fit at this time, largely asymptomatic, and ECOG performance status of zero.
So, I'd asked my colleagues was to jump right into this case. Really, I think a difficult case, in a way, in that we were hoping for a downstaging and potential attempt at eliminating the disease.
Dr. El-Khoueiry, I mean, is this typical? Do we see this happen? What are your thoughts?
Dr. El-Khoueiry:
I think, to go back, this patient unfortunately had some high-risk features at baseline, including a large tumor of 8 cm, the presence of a satellite lesion, and an AFP of 500.
And in this case, unfortunately, despite a local response where the Y-90 was delivered, there was progression in other sites. So, yes, unfortunately because of these high-risk features, this can happen. We did not achieve the downstaging that we were aiming for. So, this is a patient where at this point we would gravitate towards starting systemic immunotherapy given the upstaging now to metastatic disease or what we call Barcelona Stage C at this point.
Dr. Harding:
Dr. Kelley, is there anything else that you would now do in terms of a diagnostic workup for this patient?
Dr. Kelley:
Well, I think I would probably refer her for endoscopy or at least consider the treatment options and whether we are entertaining an option with bevacizumab included.
There's some good data in patients without any portal hypertension and a low Baveno score that perhaps we don't need to do an endoscopy in all patients before bevacizumab. This actually has been presented several times. I saw a poster at the recent EASL meeting on the topic. But, I tend to favor doing it, especially in patients with new portal vein tumor thrombus because the portal hypertension at a moment in time a month ago, 2 months ago, may change quickly when the tumor's growing into the portal vein. So, I tend to think that those patients are not usually represented fully by a dataset. And so portal vein tumor thrombus, I do get an endoscopy prior to using bevacizumab.
Dr. Harding:
That's great. And I'll ask Dr. El-Khoueiry this. There was a prior biopsy for this patient. Should this patient undergo next-generation sequencing?
What's the status of this in HCC?
Dr. El-Khoueiry:
That's actually an outstanding question. This is a disease where we currently do not have approved therapies for actionable mutations. However, as you alluded to, we have novel therapies that are being evaluated in the early-phase setting for specific subsets of hepatocellular carcinoma. One of them, for example, is the beta-catenin–mutated hepatocellular carcinoma, which is not infrequent. Estimates are about 40% to 50% of hepatocellular carcinomas having this alteration, and there are some novel therapies being evaluated in this space. So, in our practice, not that it's going to influence our first-line therapy, but we do go ahead and do next-generation sequencing either on the tumor, or at least a liquid biopsy, just to plan for potential future trials.
Dr. Harding:
Thank you so much. So, at this point, the patient did have an upper endoscopy. There's no varices, no evidence of any ulceration or potential risk for bleeding. NGS was completed. There was a Wnt-beta-catenin mutation. Now, what do we do? There's not an available trial. We have, I think, three potential options in the United States, atezolizumab and bevacizumab, durvalumab and tremelimumab, and more recently, IPI3-NIVO1.
Dr. Kelley, what are we going to do?
Dr. Kelley:
So, you stole my initial response which was look for clinical trials because, while all of these regimens are dramatic improvements upon our prior therapeutic options, none of them are yet aspirational to where we want to be. But, as you said, there are no current clinical options for this patient. This is definitely a place in the clinic where I try to employ shared decision-making as much as possible, go through the options I perceive are available to each patient, and then risks and benefits of each.
And of patients that aren't fit, who don't have an ECOG of 0 or who have high degrees of comorbidity or older, I don't usually consider the NIVO1/IPI3 option as a safe option because of the high-grade immune-related toxicity, high likelihood of needing steroids. This patient who's 64, ECOG 0, Child-Pugh A5, but has diabetes I think is marginal because we all know that if there's up to 50% chance of needing steroids, someone with poorly controlled diabetes might do poorly and have a lot of comorbidity from high-dose steroids for a month to 2 months at a time with toxicity management.
That said, if this patient's diabetes is very well controlled, as you've alluded to her being quite well fit and compensated, I would probably offer all three of those options, and I would present nivolumab plus ipilimumab as the one with the highest objective response rate and potentially longest duration of ... We can't compare the duration of response directly between trials, since they're secondary endpoints and quite difficult to obtain the confidence around, but I'd probably present nivolumab plus ipilimumab as the highest risk-reward regimen for her.
Dr. Harding:
Dr. El-Khoueiry, your thoughts?
Dr. El-Khoueiry:
No, briefly, I agree. At this point, unfortunately, because these regimens have not been compared to each other, and we do not have predictive biomarkers, we rely on the data available from the trials, the goals for the therapy, and the patient characteristics, comorbidities, as Dr. Kelley alluded to, and preference as far as willingness to take risk of side effects. How frequently are they willing to travel to the clinic? For example, the durvalumab/tremelimumab (STRIDE) regimen, once the patients have the dual combination initially, they're subsequently maintained on durvalumab alone, which is once a month. The other therapies are every 3 months, et cetera. So, it definitely shared decision-making at this point.
Dr. Harding:
That's how I approach things as well. We really have to go through all of the potential risks and benefits. Atezolizumab and bevacizumab, the first one on the scene, clearly active response rate, 30%, improvement in survival. Of course, there's a risk of bleeding. You need the endoscopy, I think, to rule that out.
The other two are CTLA-4–based and, as a result of that, probably are really more in the realm of immune-mediated toxicities.
So, as we're coming close to the end of the session, I would say that ... And it will free all of you from making a hard choice of which one you would pick. This patient presented years ago, and the only available therapy for us was atezolizumab and bevacizumab, and that's ultimately what she suggested.
I do want to ask, though, is there any case where you might use a single-agent checkpoint inhibitor or TKI before we move on?
Dr. Kelley:
Well, I'll jump in that I do sometimes use a single-agent checkpoint inhibitor in frail patients with very borderline liver function, particularly Child-Pugh B7, 8, or 9 patients for whom I perceive that an immune-related toxicity or bleeding toxicity could be a game-over type toxicity. I might start with the single agent in those patients and then lenvatinib in a patient who's had a prior transplant or has active autoimmune disease potentially.
Dr. Harding:
Dr. El-Khoueiry?
Dr. El-Khoueiry:
Nothing to add. I fully agree with that.
Dr. Harding:
Perfect. So, I think we'll move now to the key clinical takeaways. So, at the current time, the standard of care or standards of care for patients with either liver-limited disease that's not amenable to local regional therapies, the Barcelona B high-risk or metastatic Barcelona C are treated, really, now with systemic immunotherapies. The three regimens in the United States that have FDA approval for combination are atezolizumab and bevacizumab based on IMbrave150, durvalumab and tremelimumab based on the HIMALAYA study, and IP3-NIVO1 based on CheckMate 9DW. These all have been approved by the FDA. All of them are active and superior to prior TKIs.
If you are thinking about adding bevacizumab, for the most part, a screening endoscopy is something that we really should require, although there are some mechanisms which we might be able to minimize that in the future. I think the data point to the fact that we need to use shared decision-making and judge our choices based on comorbid factors, liver function, access, and so on. And so we have on the slide as the key references for you to review for the prospective data that support the use of these therapies.
Again, I thank my colleagues, Drs. Kelley and El-Khoueiry for joining me at this ASCO Post Session Roundtable. Thank you.
