Evolving HCC Treatment Paradigm: Combinations and Sequencing

Transcript: Nikolaos Pyrsopoulos, MD, PhD: Of course, I truly believe that combination is the future, with the way we see the results of the CheckMate040 with a combination of nivolumab plus ipilimumab. Nivolumab was utilized as 3 mg, ipilimumab as 1 mg. So they had the run every 3 weeks before and after that, they utilized nivolumab as maintenance therapy. For patients who did not actually have a good result with sorafenib or they broke through, they mention an overall survival of 22.8 months.

Andrew Zhu, MD, PhD: That’s very exciting.

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

Andrew Zhu, MD, PhD: Yes, I think that’s actually incredibly exciting. I think in addition to exploring a combination of a checkpoint inhibitor with a tyrosine kinase inhibitor [TKI], the I/O [immuno-oncology agent]—I/O combination also has been explored. As we mentioned in the first-line [1L] setting, the HIMALAYA study is looking at the PD-L1 [programmed death-ligand 1] antibody with CTLA4 blockade in the first-line setting. But I think with the data of nivolumab in combination with ipilimumab in the second-line [2L] setting, this is also the first time we’re showing a more favorable response rate in the range of 30% but also very encouraging overall survival data in this subgroup. I think with the data, the phase III study looking at this combination versus the standard first-line treatment, either sorafenib or lenvatinib, has been initiated. I think this will also follow the paradigm of the HIMALAYA study, examining obviously the double checkpoint inhibitor, whether it has any role in the first-line setting in terms of overall survival.

I do want to caution, though, that as we’re combining 2 checkpoint inhibitors, we definitely have to be very cautious with the safety profile of this combination. It will be very exciting to hear the presentation at the American Association for the Study of Liver Diseases meeting. I think they will present the safety profile as well in addition to the efficacy. I think as we actually design a phase III trial, it will be very nice to see whether the combination will continue to have a tolerable safety profile. As we all know, it remains to be a key factor in our treatment decision.

Nikolaos Pyrsopoulos, MD, PhD: Excellent. So the patient comes in now. So the patient has uHCC, unresectable hepatocellular carcinoma, and the first line of treatment is on board. The patient is breaking through. I/O or not I/O? This is the question.

Andrew Zhu, MD, PhD: Correct. I think definitely we have quite a lot of different approaches right now depending on obviously the regulatory approval. In my opinion, based on the positive results of the atezolizumab in combination with bevacizumab trial, it is very likely the combination will get the regulatory approval. If that’s the case, I do envision people will use the combination approach. And that would definitely consist of the I/O treatment already.

The question is really if you’re actually already having good clinical benefit but then you actually do progress, how would you logically sequence the subsequent drug? And this is very exciting. The reason being, all the data that we have for the second line up to this point are actually based on sorafenib failure, right?

Nikolaos Pyrsopoulos, MD, PhD: Yes.

Andrew Zhu, MD, PhD: We actually have no data yet after failing the combination regimen. And we even have very limited data after failing lenvatinib. For that reason, a lot of data we generate here are already historical. That’s why, when we really have to face the clinical decision, we may have to think very logically based on everything we know about the safety and everything we know about the efficacy in the unique setting. But ultimately, Nik, I do believe that with the availability of all these agents and regimens, our patients will benefit, and they will actually have different treatment options as they continue fighting for their cancer.

Nikolaos Pyrsopoulos, MD, PhD: Here is the $1 million question. So 1L, 2L—but after that, what? What’s the third line [3L] of therapy? Should we say?

Andrew Zhu, MD, PhD: Correct.

Nikolaos Pyrsopoulos, MD, PhD: The question goes TKI then I/O, and of course they are desperate. They are asking you, the physician. Go back to the TKI as the third line of therapy? What’s your take? Or if somebody has gone from TKI to TKI, how do you envision 3L? Because we don’t have anything else.

Andrew Zhu, MD, PhD: Totally, totally. All of a sudden we’re not just limited by second line. Rather, we have patients who may actually enjoy benefit beyond second-line, third-line, or even fourth-line treatment. Clearly the sequencing will be dependent on how they actually respond to the first-line treatment. What’s the regimen they have received in the first line? And then we may be able to logically sequence them subsequently. But I think we definitely need more data to guide our clinical decisions.

Nikolaos Pyrsopoulos, MD, PhD: But Andrew, 10 years ago this discussion wouldn’t have happened.

Andrew Zhu, MD, PhD: Oh, totally. Totally. We could have finished our discussion in 5 minutes. Now we can sit here for 1 hour. With that, it’s been a pleasure, Nik, to share our clinical experience, particularly your insight on the systemic treatment of advanced HCC [hepatocellular carcinoma]. I hope our audience also enjoyed this particular program. As we highlighted in this discussion, we have more treatment options for our patients, but we also have more unanswered questions that we’re facing in our clinical practice. I definitely hope that with our ongoing vigorous clinical research, we will be able to guide the clinicians with additional treatment decision making and also bring more treatment options to our patients. Thank you for joining us.

Transcript Edited for Clarity