Second-Line Therapy for Advanced HCC: The CELESTIAL Trial

Transcript: Andrew Zhu, MD, PhD: In addition to regorafenib, we also have a second tyrosine kinase inhibitor [TKI], cabozantinib. Tell us a little bit about this drug. What’s the target inhibition profile in comparison with other TKIs?

Nikolaos Pyrsopoulos, MD, PhD: This is very exciting as well, because this is the CELESTIAL trial.

Andrew Zhu, MD, PhD: Correct.

Nikolaos Pyrsopoulos, MD, PhD: This was the trial that tested patients who received sorafenib, and of course they broke through and 60 mg of cabozantinib was administered. Looking at the profile, the first thing we’re looking at is 2 tyrosine kinases that are very important. One of them is c-MET, and this is something that we targeted in the past with tivantinib, and unfortunately it didn’t pan out. c-MET is the cellular mesenchymal epithelial transcription factor, and the ligand is the hepatocellular growth factor; in other words, proliferation of the tumor. Plus, there’s AXL, which is very important for the extracellular matrix. In other words, the substrate has been inhibited by this compound. This is very appealing.

Looking at the results, the overall survival of these patients was more than 10 months, and if we look at actually the placebo, this was 8 months. Something else that was really appealing in regard to this trial is that if you look at some subpopulations like patients more than 65 years of age or patients with a very high alpha-fetoprotein—and the way we define alpha-fetoprotein is 400 ng/mL—you see that the response rate for this population was almost 20 months versus 10 months for patients who had an alpha-fetoprotein level less than 400 ng/mL. So this is a segment of the population that we need to look very closely at. Also, the adverse-event profile is somehow different from regorafenib. If somebody experienced issues with the skin, this is something you need to consider actually when you select the second-line compound as a TKI and not immunotherapy.

Andrew Zhu, MD, PhD: I think clearly with the data from the CELESTIAL trial, cabozantinib is also getting FDA approval and is becoming another second-line option for our patients. Also, it’s worth mentioning, obviously, that in the CELESTIAL trial, in addition to the prior sorafenib failure, the study also allows up to 2 prior regimens. So you have patients who fail sorafenib and also an additional treatment option. So this may actually give another treatment option for patients who fail up to two prior regimens. Tell us a little more, Nik. When the clinicians facing the decision choosing regorafenib versus cabozantinib, what should they actually be thinking? Do you really have very clear-cut advice for our oncology audience right now?

Nikolaos Pyrsopoulos, MD, PhD: Definitely this is a tough 1 because we need to take under consideration the first line of therapy, because we have 2 front-runners, and we need to investigate what the profile is of the adverse events that these patients demonstrated. And the second component, if we look at the data and cut them up the way we discussed—older patients, patients with alpha-fetoprotein, perhaps hepatitis B patients versus hepatitis C patients—there is a tendency toward regorafenib or even sorafenib as the first-line therapy, and there are some issues that people need to consider.

Transcript Edited for Clarity