Josep Llovet, MD: Let’s talk about the patients untreatable for TACE [transarterial chemoembolization] or who progressed to TACE. Years ago, when we were analyzing the population at intermediate HCC [hepatocellular carcinoma], according to the guidelines the only treatment was TACE. We realized that we can only apply these to 50% to 60% of patients. The other patients didn’t have any technical problem for applying the treatment, or they have contraindications due to the function, or they progress to TACE. Kate, do you want to say something about the indications of atezolizumab-bevacizumab and other systemic therapies in intermediate HCC, in patients not suitable for TACE or who progress to TACE?

Katie Kelley, MD: One thing to remember is that most of our systemic therapy trials have included patients based on them being unresectable and have left it to the investigator or treating physician to decide what’s not suitable for liver-directed therapy and when a patient should proceed. With systemic therapy, there haven’t been formal criteria for when a patient is truly unsuitable for liver-directed therapy and should transition to systemic therapy. The data we have for our systemic therapies are based on resectability and the treating physician’s impression of what would be best.

As you’ve mentioned, certain criteria tell us that further liver-directed therapies are unlikely to be successful, whether it’s response to prior liver-directed therapy, signs of toxicity with their prior liver-directed therapy, or tumor burden. Right now, we don’t have a concrete definition, but some are being explored in this transition to systemic therapy, such as the Up-to-7 criteria. There’s an ongoing trial called the REPLACEMENT trial, which is looking at atezolizumab-bevacizumab in patients who are beyond Up-to-7 criteria, to see if that systemic therapy will be better than another TACE treatment. We need to remind ourselves that most of our systemic therapies have shown their survival benefit and have level 1 evidence in unresectable, even intermediate patients. It reassures us that we can use these therapies if we’re on the fence or feel uncomfortable with further liver-directed therapy.

Josep Llovet, MD: Very good. Do you want to say something, Amit?

Amit Singal, MD: The idea of using systemic therapy for these patients, particularly those with a larger tumor burden, is a very interesting 1. Many of us know this analysis that was done by [Masatoshi] Kudo and colleagues with a propensity-score matched analysis. They took patients with larger tumor burden and compared them. They were treated with locoregional therapy, most commonly TACE, vs systemic therapy. In that study it was lenvatinib. What’s surprising to me is that this was 1 of the first retrospective analyses that showed patients did better with systemic therapy than with locoregional therapy. When they broke this down, they saw that patients treated with locoregional therapy had a degradation of their liver function over time, whereas those patients treated with systemic therapy had preservation of their liver function. This led to this differential survival.

Arndt, [as you said] it goes back to discussions in the tumor board. I don’t think of this as a magic number. The Up-to-7 criteria is a nice way to operationalize this, but [it’s as if] you need to take into account the tumor burden and baseline liver function. If somebody has worse liver function at baseline, and they’re going to require nonselective treatment, that patient worries me much more than somebody who comes in with very well-preserved liver function to start. This is going to be 1 of the key areas. Katie, you’re completely right. This is going to be an exciting time, but systemic therapy plays a role in some of these patients with larger intrahepatic tumor burden. It’s cutting this off in terms of an exact number or an exact tumor burden. That becomes difficult, and that’s where the tumor board can help. But in our tumor board, we’ve become more open to this than we were 5 to 7 years ago in terms of using systemic therapy and selected patients with large intrahepatic tumor burden.

Arndt Vogel, MD: Can I make 1 little comment?

Josep Llovet, MD: Absolutely.

Arndt Vogel, MD: You’re completely right that liver function deteriorates with local therapies. Liver function also deteriorates with systemic therapies. This is something we’ve learned, and we have this head-to-head trial. You mentioned the REPLACEMENT study. The ABC-HCC study has also been initiated. These trials recruit very slowly, unfortunately, but they’ll certainly help us understand prospectively. We all like Professor Kudo’s paper, but they have been retrospective. In terms of prospective data, these ongoing trials will be helpful to better define who’s a candidate for local vs systemic therapies, and the impact of the treatment on liver function. I completely agree that this is very important.

Josep Llovet, MD: It should be clear that systemic therapies have a niche in intermediate HCC to see if those patients progress to TACE. There’s no clear consensus on what progression is. There’s some consensus that at least the tumor should be exposed to twice to TACE treatment to assess response. From here, if it’s partial response, you keep going. Some guidelines say if it’s stable disease, keep going. Others say if it’s stable disease, it’s unclear if we benefit. Certainly, if the tumor progresses, the patient should be exposed. In the trials, around 20% of the patients in the front line have been exposed to systemic therapies in intermediate-stage [disease]. In the subgroup analysis, there are always very appealing data. Half already had 14 or 15 months in intermediate [stage disease]. Atezolizumab-bevacizumab has 24, 25 months. In this circumstance, it should be clear that if the patient has been exposed to the standard of care, we should move ahead with systemic therapy.

Arndt Vogel, MD: In the REFLECT study, the survival was twice as long in BCLC [Barcelona Clinic Liver Cancer] stage B or C. Can you comment on what we should do with stable disease? That’s a very interesting point.

Josep Llovet, MD: It’s questionable what to do. There’s a psychological perception for the physician. When sorafenib was the only bullet after locoregional therapy, physicians tried to keep giving locoregional. But in the end, the patient burned out, and it was too late. Now we have 6 indications. In the United States, we have 8 or 9…. The physician should not be scared about the patient not surviving. If the patient isn’t responding to TACE, I’ll move to systemic therapy.

Arndt Vogel, MD: It’s difficult to do nothing, but would you also consider doing nothing? If you have stable disease, and the tumor not growing, do you think we need to start systemic therapy?

Josep Llovet, MD: No. Stable disease means you have a viable tumor. If you have a viable tumor, I’ll keep treating.

Arndt Vogel, MD: You would treat.

Josep Llovet, MD: Yes, with TACE or with systemic therapy. If there’s tumor there, you should treat.

Amit Singal, MD: At our center we give two TACEs. If they have stable disease, meaning no response after 2 TACEs, we would move on systemic therapy. The goal with locational therapy shouldn’t be stable disease. It should be response. If you don’t achieve response after 2 TACEs—at least in our center, and this is where the AASLD [American Association for the Study of Liver Diseases] guidelines are going—the recommendation is to move on systemic therapy. You can achieve and expose your patient to these very effective therapies that are in the systemic therapy space.

Josep Llovet, MD: Katie?

Katie Kelley, MD: I’ll add 1 more comment to Arndt’s point about multidisciplinary tumor board. With our intermediate [stage disease] patients, we look at features associated with biology. Even if patients haven’t had a TACE, if we see very multifocal, very infiltrative disease, or very high AFP [alpha fetoprotein], sometimes we’ll go straight to systemic therapy for patients who have poor prognostic features for locoregional therapy.

Amit Singal, MD: Katie, those patients weren’t included in the initial TACE trials. The evidence base that we have for TACE is that those patients with very large tumors were excluded from the initial evidence base. We think of TACE as having this evidence base in the intermediate stage. But Josep, you know this better than anyone else: it was early intermediate stage. With these patients we’re talking about, we have much less data for TACE. This is where the goal of systemic therapy comes in.

Transcript edited for clarity.