Amit Singal, MD, MS, and Masatoshi Kudo, MD, PhD, comment on the role of TACE (transarterial chemoembolization) in early line settings for the management of BCLC (Barcelona Clinic Liver Cancer) stage B hepatocellular carcinoma and whether systemic therapy has the potential to replace TACE.
Masatoshi Kudo, MD, PhD: The TACTICS trial is a combination with TACE [transarterial chemoembolization] and sorafenib, pretreatment with sorafenib followed by TACE, and sorafenib is continued and then on-demand TACE is performed. For cases of hepatocellular carcinoma with up-to-7 [criteria using sum of the size of the largest tumor and total number of tumors] inpatient, and up-to-7 outpatient—most of them benefit from combination therapy with TACE and sorafenib. In that way, I assume the TACE plus targeted agents can benefit both up-to-7 inpatient and up-to-7 outpatient. Even though lenvatinib shows a high response rate by mRECIST [modified RECIST], systemic therapy itself has a limitation because if the drug is interrupted because of an adverse event, the tumor recurs.
That’s the limitation of the drug treatment. But if we introduce lenvatinib first, then perform super-selective TACE, that physically introduces ischemia and destroys the tumor cells, then that can induce pathologic CR [complete response]. Pharmacological treatment shows just a radiologic CR, not a true CR. But systemic therapy followed by selective TACE can achieve pathologic CR. It’s a true CR, there will be no recurrence. I think the combination with TACE and systemic therapy, such as lenvatinib, with a high response rate is a very good and strong strategy to achieve pathologic CR, the true CR.
Amit Singal, MD, MS: As we’ve seen advances in the systemic therapy space, I think it’s not only prudent and important for us to think about sequential therapies for patients with intermediate stage disease (ie, once again this concept of TACE failure), but it does raise the question of whether there are patients with intermediate stage disease who are better treated with systemic therapy up front. When we think about this, it’s likely that for some of these patients who have multifocal, bilobar, bulky tumors,locoregional therapy is unlikely to safely induce responses that would be of benefit. These are patients who are at high risk of liver dysfunction, post-embolization syndrome, because you would have to be giving large nonselective locoregional treatments.
We’ve now started to see some early interesting data, for example, by Masatoshi Kudo and colleagues, that suggest that some of these patients may benefit from earlier initiation up front of systemic therapy. This therapy can induce nice responses and may be able to do this in a safer manner, whether that’s with some of the TKI [tyrosine kinase inhibitors] therapies, such as lenvatinib, or that’s with immune checkpoint inhibitor therapy, such as atezolizumab-bevacizumab, that can also induce responses in a sizeable number of patients.
Finally, we’ve talked about this idea of sequential therapies, and we’ve talked about the debate of locoregional therapy versus systemic therapy, but where the field is moving is the idea of combination therapies. The combination of locoregional therapy with, for example, immune checkpoint inhibitors, is being evaluated in multiple trials at this time, combining TACE with systemic therapy, radioembolization with systemic therapy, SBRT [stereotactic body radiation therapy] with systemic therapy. I think that’s where the field is likely moving—increasing interest in these combination therapies, particularly in combination with immune checkpoint inhibitors in the hopes that, for example, you would induce more neoantigens, augment the immune checkpoint inhibitor response, and thereby help these patients.
The concept of TKI therapies being combined with locoregional therapies has been evaluated in multiple trials to date. They’ve been evaluated in the SPACE trial, the TACE 2 trial, and most recently the TACTICS trial, and most of these have failed to show a benefit of TKI therapy being combined with chemoembolization or other locoregional therapies.
Most of these trials have looked at the combination of sorafenib with locoregional therapy. I know there’s 1 trial that looked at lenvatinib in combination with locoregional therapy, which suggested potential benefit of lenvatinib with TACE. But I think although this may be a benefit, in general, the field is more interested in the combinations of immune checkpoint inhibitors with locoregional therapies, particularly in light of the IMbrave150 data that show superiority of atezolizumab-bevacizumab compared to TKI-based therapies.
Transcript Edited for Clarity