Optimizing Treatment Selection in Liver Cancer - Episode 14

Evidence With Checkpoint Inhibition in HCC

Transcript:Ghassan K. Abou-Alfa, MD: Wait, we’re not really done discussing how much, really, is going on in the field. We have to talk, absolutely, about checkpoint inhibitors. What’s the story with nivolumab?

R. Kate Kelley, MD: Immunotherapy is certainly the theme of the day in medical oncology, in particular across tumor types, and liver cancer is no exception. Nivolumab is a PD-1 inhibitor monoclonal antibody that helps your immune system and your lymphocytes to remove an inhibitory stimulus from stroma or tumor. It allows immune recognition of a cancer, and allows the immune system to fight the cancer upon relief of that inhibition. PD-1 inhibitors are now labeled in at least 7 different cancers, including Hodgkin’s lymphoma, kidney cancer, and lung cancers such as small cell lung cancer. The list is growing by the day. Originally, liver cancer lagged behind, given concern about immune toxicity and the risk of autoimmune hepatitis arising in patients that already have a compromised liver function.

The first study in HCC was with nivolumab. It was called the CheckMate-040 study, and it did a very careful job at separating out the causes of liver cancer into 3 different non-viral buckets: patients without viral hepatitis, patients with hepatitis B infection, and patients with hepatitis C infection. This is so that each subgroup could be very carefully evaluated for potential immune response—not only immune response against the tumor, but also potential immune toxicity that would be a big problem in this compromised or hepatic dysfunction population at baseline. And the CheckMate-040 study has now been presented several times over the past 2 years. It has accrued upwards of 250 patients in its expansion cohort, and it has showed a really provocative response rate of about 15% overall across these 2 subgroups—perhaps numerically higher in the non-viral group, but not yet significantly different between these 3 cohorts of non-viral hepatitis B and hepatitis C.

So, that’s a very high response rate by RECIST in the liver cancer population. Not only is the response rate high, but it’s been a durable response with a pretty long median duration, to date. That has prompted a large randomized phase III trial, CheckMate-459, to follow up on that non-randomized, or single arm, phase II experience.

Ghassan K. Abou-Alfa, MD: Other than nivolumab versus sorafenib, which is the CheckMate-459 trial in a first-line setting, it also appears to be that there is interest in pembrolizumab in the second-line setting. Can tell us about that as well?

R. Kate Kelley, MD: Right. The nivolumab experience has led to other PD-1 inhibitors and PD-L1 inhibitors being explored in liver cancer, including pembrolizumab, in a randomized study, compared to placebo, in second-line as well as a single arm study. Those are the KEYNOTE-240 and KEYNOTE-224 studies that are also accruing very quickly, and are expected to report in the near future. And there are some immunotherapy combinations. Just like we’ve seen reach approval in lung cancer and melanoma, the combination of a PD-1 or PD-L1 inhibitor with another type of checkpoint inhibitor, called CTLA4—an older family of drugs that have been approved for a while now in melanoma and prostate cancer. The combination of checkpoint inhibition by PD-1 or PD-L1 and CTLA4 is now being studied in liver cancer with various combinations of drugs. We’re very excited to see how the results will play out.

Ghassan K. Abou-Alfa, MD: Absolutely. What Katie is referring to is durvalumab plus tremelimumab versus durvalumab alone versus tremelimumab alone, which is CTLA4 plus PD-1 versus CTLA4 alone versus PD-1 alone. As you can see, this field is really becoming quite extensive—enough that it probably will not give fair justice for the number of trials that are going in that field. For me, my very simple understanding of immunotherapy is that the T cells are like cars in New York City, and the checkpoint inhibitors are the light signals. And one day, in New York, while the cars are on the street, you can remove all those light signals. What does that mean from the hepatology standpoint? There are a lot of concerns there.

Laura M. Kulik, MD: I use a similar analogy, except I use brakes as opposed to the lights.

Ghassan K. Abou-Alfa, MD: There you go.

Laura M. Kulik, MD: The concern has been with hepatitis C and hepatitis B. With hepatitis C, there does not seem to be a big concern in terms of what has been found in using these immune checkpoint inhibitors. However, in hepatitis B, they’ve all been, for the most part—at least with nivolumab in hepatitis B patients who are on medicines—antivirals with a viral load less than 100. There’s still concern if you cannot drive that viral load down, and if you are stimulating the immune system. Hepatitis B is known for causing problems by stimulation of the immune system, and for causing this fighting between the immune system and the virus. So, that remains to be seen. I’ve tried to send several patients with hepatitis B who are on medications, who should have negative viral loads, and are still positive. And there may be some interaction with the virus that it is able to hide within the tumor. You can’t get those patients’ viral load down, and therefore, they’ve not been able to participate in these trials.

In terms of autoimmune hepatitis, you wouldn’t expect that someone who has underlying liver disease from other causes should be at a higher risk, necessarily, of developing autoimmune hepatitis from an immune checkpoint inhibitor. Perhaps, in hepatitis C, there is some slight overlap. You could have positive ANAs (antinuclear antibodies), and you can see signs of autoimmune hepatitis that is being driven by the hepatitis C. Will that increase the risk? I think that remains to be seen.

Ghassan K. Abou-Alfa, MD: If anything, what we’re trying to allude to here is that this is, no doubt, a highly promising field. As we just heard, in many indications, it has already proven its effect. But in HCC specifically, and similar to others, this is not necessarily as simple as we might think it is. This is really an unleashing of the immune system, and not necessarily with control. With this said, it’s important to try to wait on those trials. We contribute to those trials, and if anything, patients are very eager to contribute and be part of those studies. I would resist using those drugs out of a clinical trial. If you’re really squeezed, however, just make sure you know what you’re doing because there is no question that transaminitis, pneumonitis with nivolumab, etc, are really things that have to be understood and taken care of, thus avoiding any complications.

Transcript Edited for Clarity