Two Options for Checkpoint Inhibition in HCC

Transcript:

Ghassan K. Abou-Alfa, MD: We heard so far about 3 TKIs [tyrosine kinase inhibitors] in the setting of third-line, being regorafenib, second is cabozantinib, and thirdly is ramucirumab. And quite fascinating that the evaluation that we heard from all of us is that regorafenib, there’s this kind of conditional requirement of progression on the sorafenib that led to a potential positive outcome using regorafenib. And understandably, tolerance will come into play as well over here. And as we heard from Andrew that, yes, they might look very similar, very subtle differences, but they could probably make the difference as we heard in regard to TIE2 [pathway], and what have you.

Number 2 is cabozantinib. Interestingly, cabozantinib has shown its positive impact and, by the way, it happened in second-line and even in third-line. In other words, patients were required to get prior sorafenib but they could have gotten probably another line of therapy, and still the outcome was positive. And thirdly, we heard about the ramucirumab that no doubt is, or has shown an improvement in survival in specifically the patients with high AFP [alpha-fetoprotein] that’s more than 400 [ng/mL]. How is this going to be used and applied? I think some guidance is already in place. Again, go back sorafenib followed by REGO [regorafenib], so it’s like they are really tied up together, per se. But on the other hand, for the AFP, if it’s more than 400, then ramucirumab could be the choice, pending of course the FDA approval for that.

So I would say that’s going to evolve as we go in regard to the ultimate choices of the use of those different TKIs. Interestingly, however, what we’re facing with all those TKIs, and already we mentioned 5 of them—2 in first-line and 3 in second-line—the big story, or the other big story I would say, came from the checkpoint inhibitors. And as we heard from the beginning from Rich, there are already 2 of them conditionally approved by the FDA and available in the market.

And it will be intriguing to hear a little bit more about those 2 before we dissect further the question of the checkpoint inhibitors. And I’ll start with Katie and, of course, the data that we … heard most about in the beginning were that of nivolumab. So tell us first, what’s nivolumab; like immunotherapy, then what? What is it?

R. Kate Kelley, MD: The nivolumab is one of several drugs now in the family of programmed [cell] death [protein] 1 immune checkpoint inhibitors, or PD-1 inhibitors. And it was actually the second checkpoint inhibitor studied in HCC, the first being a CTLA-4 [cytotoxic T-lymphocyte—associated protein 4] inhibitor called tremelimumab, a while back in just hepatitis C in a very small cohort, which had intriguing results but not enough to move forward at that time. So the nivolumab story begins as CheckMate 040, a single arm; rather I should say a checkpoint inhibitor monotherapy study that started out as a phase I/II safety study to really test the safety of immune disinhibition with a checkpoint inhibitor.

You asked, what is a checkpoint inhibitor? And I think that does bear repeating even to an oncology audience. A PD-1 inhibitor blocks an innate checks and balance on our own immune system and it allows T cells to be activated by MHC [major histocompatibility complex] bearing an antigen that they recognize in their environment rather than being shut down by an inhibitory signal. And so it blocks that inhibitory signal and lets our T cells recognize potential for an antigen of a tumor in this case. And so the first PD-1 checkpoint inhibitor is nivolumab, which was studied in CheckMate 040.

Ghassan K. Abou-Alfa, MD: Fair enough. And this definitely had a nice response, but if I were to understand what really was most intriguing is not only the response rate, but the duration of response. And then we saw something relatively similar as outcome, and, Andy, you can tell us about your data on pembrolizumab.

Andrew X. Zhu, MD, PhD: So pembrolizumab is another PD-1 antibody. We actually tested that drug very similarly to the nivolumab experience in a population who had advanced HCC and they failed sorafenib, in a population with different etiology—hepatitis B, hepatitis C, uninfected. And in the whole cohort of 104 patients, we observed a very solid 17% response rate. And as you correctly pointed out that very similar to nivolumab, our data also suggest, if you respond, the duration of response tends to be very impressive. And we have patients that actually stay on trial for a prolonged period of time.

So the safety profile is very similar to what we anticipate for this class of drug, and I think with that data, FDA also approved this agent in the accelerated approval setting in the second-line. So all of a sudden we have 2 checkpoint inhibitors that we can apply to our patients, which is fantastic news for our patients.

Transcript Edited for Clarity