Unmet Needs in the Treatment of Advanced HCC in Second-Line and Beyond

Anthony B. El-Khoueiry, MD: As a group, let’s chat briefly about some challenges and unmet needs in the second-line and beyond setting. I’ll summarize some that have come up in our conversation and see if there’s anything else to add. We’ve all said that all of our approved therapies in the second line or beyond were studied post sorafenib. There’s certainly an area of unmet need for drug development post-IO [immuno-oncology] combinations. We need new agents, more drug development, and more data on how to sequence these therapies. I also heard about the absence of data as far as using IO post-IO progression. There are limited data. There are maybe some ongoing small studies, and more data are needed in that space. Is there anything else anyone would like to add?

Nicole Rich, MD: Dr El-Khoueiry, one of the areas of unmet need is that Child-Pugh B in first and second line is an area where we don’t have the data. We have some evidence of safety with IOs, particularly with nivolumab in that setting. But that’s going to be an area that we’ll need more data on.

Anthony B. El-Khoueiry, MD: Very good. Because we keep talking about this topic and it’s important to all the practitioners, I’d like the hepatologist to stop me if I say anything wrong, but it’s important to realize that underlying liver cirrhosis is a competing risk of death in all of these patients. It’s important that we don’t subject patients to anticancer therapy unnecessarily when they’re going to die of their liver disease. Child-Pugh C patients, patients with Child-Pugh B who have refractory ascites requiring paracentesis, and those with active hepatic encephalopathy probably shouldn’t get anticancer therapy. They will die of their liver disease. This is an important example of the principle of do no harm and provide supportive care. Is there anything from the hepatologist to add on that?

Pierre Gholam, MD: I have nothing to add to that. You summarized it very well. I don’t think there are a ton of patients with Child-Pugh C cirrhosis who we’re sticking our necks out for and treating, although I may be mistaken. The opposite is what’s happening. There are many patients who have opportunities for treatment fairly early on with systemic therapy, including in the intermediate stage, where they may have very bad biology but no macrovascular invasion or extrahepatic spread, and we’re not venturing out to treat those patients. But your comments are absolutely on point. A patient who has terminal liver disease need not have the additional burden of the toxicity of cancer therapy to make their quality of life even more miserable.

Nicole Rich, MD: The only thing that I’d add is that especially given the high response rates with some of the exciting new therapies, we have to also consider the possibility that some of these patients will be able to be down staged, even potentially for a liver transplant, even after getting an IO. There are data coming out of Mount Sinai Health System, New York, New York showing that IOs appear to be safe in the pretransplant setting. There was a series of 10 patients treated with nivolumab who, I believe, to date have had no episodes of rejection in that cohort post-transplant. Referral to a transplant center—particularly if the patient has no evidence of extrahepatic disease and has had a response to IO—is very reasonable, because ultimately that’s going to cure their cirrhosis, their underlying liver disease, and the HCC [hepatocellular carcinoma].

Anthony B. El-Khoueiry, MD: What was the washout after giving nivolumab prior to transplant that was reported?

Nicole Rich, MD: At the Mount Sinai series, there was no specified washout period. Someone correct me if I’m wrong, but I believe 2 of the patients received nivolumab right up until time of transplant in that series. In terms of practice and what I’ve heard—I’d be interested to see what Dr Gholam says as well—many centers are talking about a 3-month to potentially 6-month washout period being the standard, but realizing that the half-life of nivolumab may not be representative of the impact on the immune system and the potential for rejection post transplant.

Anthony B. El-Khoueiry, MD: To set the stage here, this is an off-label usage. Dr Gholam mentioned the high rejection rate if you give anti–PD-1 therapy to someone who’s received a transplant. Here, we’re talking about giving it pretransplant to downstage. This should be done in a multidisciplinary setting, preferably in a tertiary care center. Dr Gholam, do you have anything to add?

Pierre Gholam, MD: No, except to say that our understanding of the resetting of the immune system after treatment with immunotherapy remains somewhat imperfect. A very good example that our medical oncology colleagues and hepatologists who attend and are consulted by medical oncologists would attest to is that oftentimes patients have a response to corticosteroids when they develop immune-mediated events—in our case, specifically autoimmune hepatitis—only to have a relapse or a flare—whatever you want to call it—many weeks later. This clearly isn’t similar to drug-induced liver injury that creates an immune-mediated type. This is an imprinting on the immune system that goes far beyond the half-life of the drug. Tread carefully here, but who knows? Maybe this will become something we’re comfortable with in many years to come.

Anthony B. El-Khoueiry, MD: Certainly, more studies are needed as far as deploying the anti–PD-1 combinations as a downstaging modality to transplant. This is very early experience and more needs to be seen.

Transcript Edited for Clarity