Ghassan K. Abou-Alfa, MD: This brings me, Anthony, to your very important story about nivolumab. And the funny thing is, you personally contributed to, ultimately, the FDA approval of nivolumab in the second-line setting. And now you know Ruth and I are having a great time here talking about 24 months, and great response to a TKI, and then you come from the left field with a drug called nivolumab. So, tell us a little more about that.

Anthony El-Khoueiry, MD: So, nivolumab is the anti—PD-1 antibody, one of the checkpoint inhibitors that have shown efficacy, and one of the many that have shown activity in many tumor types. You know if we go back 4 or 5 years ago, we never thought that we would test these in liver cancer because we always thought the liver is such a tolerant organ, there is no immune suppression. But we’ve learned over time that liver cancer, like other cancers, has many mechanisms by which to shut down the immune system and prevent it from recognizing the cancer and acting against it. So, the goal of nivolumab is to remove one of those breaks, one of those checkpoints—the PD-1–PD-L1 interaction—and reawaken the T cells to recognize the cancer and act against it. So, the evaluation of nivolumab so far has been as part of the phase I-II study known as CheckMate-040, which ultimately led to the accelerated approval in September of 2017.

Briefly, the dose-escalation part of the study, which was about 48 patients, taught us that this was a safe approach, that the side effect profile of nivolumab in liver cancer was no different than other tumor types. And the dose that was adopted as a recommended phase II dose was the same as other tumor types: 3 mg/kg or the fixed dose of 240 mg. Subsequently, there was an expansion of 4 different cohorts that totals 214 patients, where we learned a little bit more about the activity, and that was published already with an overall response rate of 20%.

You mentioned the survival excitement with the sequence of sorafenib followed by regorafenib, which is, again, certainly exciting. Some of the early survival data with nivolumab come from an analysis we did by looking at the sorafenib-naïve patients—80 of them in this phase I-II study—and their median survival was about 28 months. And then the patients who were sorafenib experienced, most of them who had progressed on sorafenib, their median survival was about 15 months. So, these are very promising exciting numbers compared with what we’re used to. And, again, hopefully it offers another option to patients.

Ghassan K. Abou-Alfa, MD: Great. But Catherine, probably we’re now like, “Whoa, these oncologists who are giving TKIs, some side effects, we can handle it, we’ll talk about it,” but now we’re talking about changing immune modulation and the immune system, and you coming from the world of liver transplant, what do you think is there to be of concern? Because, especially from the toxicity standpoint, no question, this is a great drug, as we just heard from Anthony. But at the same time, it’s not necessarily a walk in the park for everybody. Tell us what will be your concerns, from the liver standpoint, in regard to the application of a checkpoint inhibitor?

Catherine Frenette, MD: I was not surprised to see the immune checkpoint inhibitors have activity in HCC because we see people who have liver transplant for cancer and then recur post transplant. When they’re on the immune suppression, the cancer progresses a lot faster than patients who are not on immune suppression. So, it does make sense that this interaction with the immune system would have an effect. The concern is for the patient who has not been transplanted or doesn’t have any autoimmune problems, there have been reports of autoimmune hepatitis and specific liver damage with these checkpoint inhibitors. Now, the percentage is low, less than 5%. However, it can be quite severe and patients can actually go into liver failure because of the autoimmune issues with the checkpoint inhibitors.

In the transplant population, we do not want to have anything to do with immune checkpoint inhibitors. After transplant, there have been several studies of patients getting the checkpoint inhibitors. Say they’ve had a kidney transplant. Now they have metastatic melanoma and are rejecting that organ. Now if you have a kidney transplant and you reject it, you go back on dialysis. But if you have a liver transplant and you reject it, you’re in trouble. So, that’s a big concern. We also don’t know how long the effect on the immune system lasts. We don’t know what will happen if patients get an immune checkpoint inhibitor, have a response, and now they’re potentially somebody that could go to transplant. What would happen with those patients? So, at this point, we’re avoiding immune checkpoint inhibitors in anyone that could potentially could go on to a liver transplant down the line.

Ghassan K. Abou-Alfa, MD: This is very important. Along that line, would you consider anybody who might not be eligible for checkpoint inhibitor other than what you had suggested about the potential transplanted patients?

Catherine Frenette, MD: In terms of patients who would not be eligible for a checkpoint inhibitor, other than the potential transplant patients, I would worry about patients who have autoimmune diseases like autoimmune hepatitis, PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), or rheumatoid arthritis. So, really any autoimmune diseases. Because we have seen patients who get the immune checkpoint inhibitors and can have very bad flares of their autoimmune diseases they already have underlying.

Ghassan K. Abou-Alfa, MD: That’s very, very important.

Transcript Edited for Clarity