Frontline I/O Therapy for HCC: Results From CheckMate459

Transcript: Andrew Zhu, MD, PhD: Moving on, we actually have a very active investigation of checkpoint inhibitors, even in the first-line setting, based on the CheckMate040 data showing very good response data, particularly durable responses, for nivolumab. We all know CheckMate459 investigated the survival advantage of nivolumab versus sorafenib in the phase III trial. That study, after quite a few years of effort, was actually recently presented. Perhaps you can share with our audience the results and also the implication of a CheckMate459?

Nikolaos Pyrsopoulos, MD, PhD: Absolutely. Now that our appetite increased once we had the lenvatinib on board, we looked at the use of sophisticated immunotherapy. Of course, the results of second-line treatment appear to be more appealing. So it was about time to investigate the utilization of nivolumab versus the front-runner, which happened to be sorafenib at the time the trial was designed.

Of course, there was a signal that perhaps this can be very beneficial. The trial enrolled a number of patients where they utilized sorafenib versus nivolumab. But at the end of the day, apparently the overall survival rate was 16.4 months versus roughly 15 months for the sorafenib. It looks like the old runner is still active and is still working. At the same time, nivolumab did not present what everybody anticipated. This is something we need to take under consideration, because sometimes the adverse-event profile is different for these kinds of medications.

Andrew Zhu, MD, PhD: Were you surprised about the results for CheckMate459?

Nikolaos Pyrsopoulos, MD, PhD: Yes, I am. What about you?

Andrew Zhu, MD, PhD: Yes. Obviously this is a study all of us have been waiting for given the excitement for checkpoint inhibitors in hepatocellular carcinoma. We know this class of drugs can clearly produce durable responses in about 15% of the patients. Nevertheless, I think the study definitely failed to demonstrate the statistically significant improvement for the overall survival.

On the other hand, I do think none of us can deny the true value for checkpoint inhibitors, because we have seen it in our clinical practice. And definitely, you have about 15% of the patients who will respond. When they do, they will have significant clinical benefit. These patients can actually do well for a prolonged period of time.

Perhaps the challenge for us is really to figure out who are those 15% of the patients. Are there any biomarkers that we can actually apply to select those patients? Also, what would be a good end point, so we can definitively say that this class of drugs will benefit patients?

Nikolaos Pyrsopoulos, MD, PhD: Do you believe that treating patients with a multikinase inhibitor might induce some other substances, like we know, c-MET—the mesenchymal-epithelial transition factor with the ligand of the hepatocyte growth factor—actually has been induced by some observations when we’re looking at the lenvatinib data. Do you believe that this can induce and make the checkpoint inhibitors more potent by looking different?

Andrew Zhu, MD, PhD: Yes, great question, Nik. I think how the checkpoint inhibitors will actually be functioning, either better or actually worse, after the TKI exposure is probably a question where there are a lot of ongoing investigations right now. I think theoretically, having the TKI on board perhaps will change the immune milieu, if you will. That may actually alter some of the key immune checkpoint inhibitor molecule expression, which in turn may actually make the PD-1 [programmed cell death protein 1] antibodies work differently. But I think the data should actually be continued till trial results come out. And this is actually a very exciting area of a lot of investigations.

Transcript Edited for Clarity