Advanced HCC: Trial Data for Frontline Combination Therapy

Transcript: Andrew Zhu, MD, PhD: For the first-line setting, Nik, we know nivolumab alone is not the single regimen. This is perhaps the most exciting area of clinical investigation. A lot of the combination treatments are actually entering this space. We have quite a few different strategies. We have the checkpoint inhibitors in combination with antiangiogenics: either monoclonal antibody against VEGF, or actually tyrosine kinase inhibitors with targeted inhibition, including VEGFR2. So we have the IMbrave150 trial combining atezolizumab, a PD-L1 [programmed death-ligand 1] antibody, with bevacizumab, an anti-VEGF antibody.

Nikolaos Pyrsopoulos, MD, PhD: What do you think about this combination?

Andrew Zhu, MD, PhD: Very exciting results. As you know, in the early phase I study, this regimen had a very impressive response rate in a very small subset of patients. For that reason, the FDA actually designated this as a breakthrough therapy. As time continues, we have, obviously, the enlarged cohort, where the response still sustained at about 30% and the response is very durable.

Perhaps more exciting, with the early impressive response rate, the phase III study, the IMbrave150, was actually designed looking at the combination of atezolizumab with bevacizumab versus sorafenib in the treatment-naïve first-line setting. The study was really looking for both the improvement of overall survival [OS] as well as for progression-free survival [PFS] as coprimary end points. As we heard from the press release not too long ago, the study actually met the primary end point, both for improved OS and for PFS.

This is actually the first combination regimen that demonstrated the improved survival compared with the standard sorafenib treatment. I think we’re very eager, obviously, to know the maturity of the data. This will be presented at the end of this month at the ESMO [European Society for Medical Oncology Asia 2019 Congress] meeting. So we will know the result in detail. But I think if this is the case, this has significant implication for how we treat our patients in first-line settings.

Nikolaos Pyrsopoulos, MD, PhD: Andrew, how do you feel about the combination of a PD-1 [programmed cell death protein 1] inhibitor like atezolizumab plus one of the TKIs, like cabozantinib?

Andrew Zhu, MD, PhD: This is obviously a very exciting question. Similar studies, as you know, have been designed. We have another phase III study looking at atezolizumab in combination with cabozantinib, with a comparator arm also being sorafenib. They do actually have a third arm of cabozantinib in that study, COSMIC-312. Likewise, as you know, the other combination, pembrolizumab with lenvatinib, is also showing some very striking response data in a first-line setting and the response rates are also up to 40% per modified RECIST.

Nikolaos Pyrsopoulos, MD, PhD: Yes.

Andrew Zhu, MD, PhD: This has actually also received the FDA breakthrough designation. The phase III study looking at that combination, with a control arm of lenvatinib, is currently ongoing. So I think we have some very interesting stuff, yes.

Nikolaos Pyrsopoulos, MD, PhD: Yes. How do you feel if now about the mix with transarterial chemoembolization [TACE]?

Andrew Zhu, MD, PhD: I like this idea. As you know, locoregional therapy has been a very active treatment option for our patients. On the other hand, we also have actually investigated quite extensively combining locoregional therapy, particularly chemoembolization or radioembolization, with systemic therapy. As you know, in the setting of sorafenib, that effort has universally failed. We have actually not been able to demonstrate that using sorafenib after TACE, or concurrently with TACE, is helping these patients.

Likewise, I think the direct comparison with radioembolization with sorafenib also has failed. But I do think in the setting of developing immunotherapy, there’s probably additional advantage, at least theoretical advantage, looking at this class of agents with checkpoint inhibitors. Because this type of locoregional therapy can clearly expose the tumor antigen with treatment, and that may actually in turn enhance the PD-1 antibody efficacy. But I think the relevant clinical trials are currently ongoing, and we’ll wait to see the results.

Nikolaos Pyrsopoulos, MD, PhD: I’m very curious to see the HIMALAYA trial as well.

Andrew Zhu, MD, PhD: That’s fantastic. I’m glad you mentioned that. In addition to the PD-1 versus antiangiogenics combination, you’re right. We’re also investigating the dual immuno-oncologic combination. Tell us a little about the HIMALAYA trial.

Nikolaos Pyrsopoulos, MD, PhD: This is wonderful because we have 2 different classes of medication—PD-1 and of course the tremelimumab—coming together and trying to block different stages of the tumor, carcinogenesis and the proliferation of the tumor. And there is a signal that the overall survival can be actually much improved in comparison with sorafenib.

Andrew Zhu, MD, PhD: Correct.

Nikolaos Pyrsopoulos, MD, PhD: So the trial is ongoing, and we are looking forward to the results of this.

Transcript Edited for Clarity