ESMO Asia 2025 | Systemic therapy & locoregional therapy in intermediate stage HCC

So this, in theory, was longer because it was a 20-minute oral presentation, but I discussed therapy plus local regional therapy in patients with intermediate stage HCC. Now, we know that the standard of care for patients with intermediate stage HCC is TACE or any other local regional treatment, for instance, also TARE or radioembolization. But we also know that there are patients who don’t benefit from the use of local regional therapy. And indeed, in the ESMO guideline for patients with intermediate stage HCC, there are different options: local regional therapy alone, the combination of locoregional therapy and immunotherapy combinations, so locoregional therapy and systemic therapy. And also for patients who are unsuitable or progress on locoregional therapy, there is also the possibility of a systemic therapy. And this is related to the fact that the heterogeneity, that intermediate stage HCC is very heterogeneous. So we have patients with a few nodules in the liver, patients with multiple and large nodules in the liver, patients with different liver function. We have patients with comorbidities, patients who have to take concomitant medications. And so there are very, very different groups of patients in the same stage that is called intermediate stage HCC or BCLC. There are patients where the local regional procedure is technically feasible, but it’s not oncologically the best approach. We know that some patients do not benefit from local regional therapy. And so for these patients, we may consider to use systemic therapy or the combination of systemic therapy and local regional therapy. And for the combination of systemic therapy and local regional therapy, there are data supporting the rationale, their biological rationale for combining especially immunotherapy and anti-angiogenics with local regional therapy and especially with TACE because we have the most important data that we have are with TACE. So at ASIA 2025, I presented the data that we have for systemic therapy alone. And indeed, we have a subgroup analysis from IMBRAVE 150. So from the phase three trial of atezolizumab and Bevacizumab in the advanced setting. And in the subgroup of patients with BCLC-B stage HCC, there was a benefit from atezolizumab and Bevacizumab, so systemic therapy without any local regional therapy. Then there is a Japanese phase two study called the replacement study that enrolled patients with intermediate stage HCC with a large and important high tumor burden in the liver. Indeed, they were beyond up to seven. And also in these patients, there is a clear benefit from atezolizumab and bevacizumab, so administered as a systemic therapy alone without local regional therapy. Then at ESMO, so not ESMO Asia, but ESMO 2025, the interim analysis of the Phase 3B ABC-HCC study was presented. The ABC-HCC study is an investigator-initiative trial, so an academic trial, that tested in patients with intermediate-stage HCC suitable for TACE from a technical point of view, but with, for instance, also with a limited vascular invasion, VP1, VP2. So patients that we know that maybe in clinical practice are not the best candidate for TACE. But anyway, patients who are suitable for TACE. And in this trial, patients were randomized between TACE and systemic therapy with atezolizumab and bevacizumab. And the primary endpoint of the study is the time to failure of treatment strategy. Indeed, the authors presented at ESMO the interim analysis of this trial that was pre-planned. And there is a clear benefit from atezolizumab and bevacizumab versus TACE. The curves are very well separated. So this is an important data supporting the use of systemic therapy. However, this is an interim analysis. The study is still ongoing and we have to wait for the final analysis. And if the final analysis will confirm this data, systemic therapy will be an option also in clinical practice for patients with intermediate stage HCC. So these are the data, most of the data that we have for the systemic therapy in intermediate stage HCC. The other possibility is to combine local regional therapy with systemic therapy. And first, we have a randomized phase two study that is the CARS005. That is a study conducted in China that tested in patients with intermediate stage HCC and also limited vascular invasion, VP1, VP2. So technically they are advanced, but also in other trials like the ABC, HCC, minimal vascular invasion was allowed. So anyway, in the CARES-005, patients were randomized between TACE and TACE plus camrelizumab and rivoceranib, so another immunotherapy combination. And there is a clear benefit in progression-free survival for the combination, and also in terms of objective responses. There is no benefit in overall survival, but this is something that we will see also in other trials. And in terms of safety, the combination has a favorable safety profile. Of course, we have the adverse events with the TACE and also the adverse events associated with the immunotherapy combination. Then we have three phase three studies testing different immunotherapy combinations with TACE. The first one published this year in The Lancet is Emerald I. That is a phase three study that tested TACE alone, TACE plus Durvalumab plus Bevacizumab and TACE plus Durvalumab. TACE plus Durvalumab, so TACE plus immunotherapy versus TACE have not positive results. So the combination of TACE and Durvalumab is not superior compared to TACE. But the primary point of the study was to test progression-free survival for patients treated with a TACE, Durvalumab and Bevacizumab compared to TACE alone. And the trial is positive. There is a clear benefit in progression-free survival. There is also a benefit in objective response. The combination, as mentioned for the previous trial, is well-tolerated with a favorable safety profile. And there are some subgroup analyses that show that the benefit of TACE plus Durvalumab plus Bevacizumab compared to TACE alone was maintained regardless of albumin grade, so regardless of the liver function, regardless of the type of TACE, c-TACE, conventional TACE with Lipiodol or DEB TACE, and also according to the tumor burden. So these are data generated during 2024 and 2025. Then we have the LIP012, that is another phase three study in a pure intermediate stage HCC population that tested the combination of TACE plus lenvatinib plus pembrolizumab versus TACE alone. And again, there is a clear benefit in progression-free survival. There is a very high response rate. The overall survival data were not mature, but very recently a press release by the pharma companies that sponsored the study announced that the overall survival endpoint was not met. So there is no benefit in overall survival. For the other studies, we don’t know yet the data in terms of overall survival. In terms of safety, similar comment, the safety profile is tolerable. There are the adverse events associated with TACE and the adverse events associated with the immunotherapy combinations, but no new safety signals and no synergistic toxicity. Then the third phase three study is the TALENTACE, presented at ESMO 2025 and not yet published in full. And this is a trial conducted in Asia, mostly in China, that tested on-demand TACE, so a different way of administering TACE, on-demand TACE alone, or in combination with atezolizumab plus bevacizumab. Once again, patients with VP1 and VP2 were included, so patients with a limited vascular invasion. And once again, the primary endpoint of this study is progression-free survival, and there is a benefit, a statistically significant benefit in progression-free survival for TACE plus atezolizumab plus bevacizumab compared to TACE alone. There is also a clear benefit in objective response rate. And same comment in terms of safety, no new safety signals. The combination also of TACE plus atezolizumab plus bevacizumab is quite well tolerated. What is important here for all these studies is the benefit in progression-free survival and also the benefit in objective response, because we can consider to potentially convert patients with intermediate stage HCC to curative treatments. If there is a high response rate, then maybe there is the possibility for surgery or even liver transplant. So this is something that we have to keep in mind, even if we don’t have yet, at least for some of these studies, a benefit in overall survival. These studies are quite heterogeneous, so it’s difficult to compare one with the other. But overall, there is a benefit in progression-free survival and overall response rate. There are several other trials ongoing, both combining TACE and different immunotherapy combinations, and other trials combining TARE or Y90 or SIRT and immunotherapy, or even SBRT or PBT, so other types of local regional therapy with immunotherapy, either stereotactic body radiotherapy or proton beam radiotherapy. Considering all these different trials of these potential future different options, it’s very, very clear that the multidisciplinary approach is mandatory for patients with HCC. We cannot decide the treatment without discussing with all the physicians involved, the oncologists, the radiologists, the pathologists, the gastroenterologists, the surgeons. All the different specialists should be involved in the decision. So overall, or in conclusion, we know that intermediate stage HCC is very heterogeneous. TACE is still the standard of care, but we have data supporting the use of systemic therapy alone in some groups of patients with intermediate stage HCC, and we have data supporting the combination of TACE and different immunotherapy combinations. So this is not standard clinical practice, but we are generating data supporting this. There are several open issues. Indeed, we have, as I said, there are ongoing trials, so we’ll have more data in the future, and we don’t have overall survival data for most of the trials. The only trial with negative overall survival data, at least so far, is the LEAP-012. We don’t have biomarkers and clinical factors, so we don’t have clear factors based on which we can select which patients might benefit from local regional therapy alone or the combination or systemic therapy. So this is something that we have to generate. We don’t know how to define the sequences after systemic therapy or TACE plus systemic therapy when administered in the intermediate stage. We have to better clarify how to treat patients with a clear downstaging. So maybe surgery, maybe liver transplant, we don’t know yet. We need to better clarify the safety profile of the combinations, the quality of life. And also for these different approaches, we have to consider potential financial toxicity and potential healthcare resource utilization that are not the same as with TACE alone. So different aspects that we will have to consider in the future if these new options will become a standard of care. And once again, as I said, the multidisciplinary approach is key to offer the best treatment to each patient with HCC. Thank you so much for your kind attention. Brilliant, thank you. And so thirdly, what are some emerging data and strategies.

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