Richard S. Finn, MD: Michael, we have other TKIs [tyrosine kinase inhibitors] in liver cancer, specifically in the second-line setting—regorafenib and cabozantinib—that were approved based on randomized data vs placebo. Both had similar hazard ratios—in the 0.6, 0.7 range. They’re both VEGF receptor inhibitors, plus. Specifically, cabozantinib has activity against c-MET and AXL, which is unique among the TKIs. But again, their adverse-effect profiles are fairly similar.

And the approval of atezolizumab-bevacizumab in the frontline setting has changed or disrupted our phase 3 data sets, right? None of the second-line drugs was studied after prior treatment with atezolizumab-bevacizumab. Even the approval of lenvatinib disrupted that a bit. They all followed sorafenib.

We have ramucirumab, as you commented on earlier, for patients who have an elevated AFP. That drug targets VEGFR2. We also know that bevacizumab targets VEGF. So a patient gets atezolizumab-bevacizumab in the frontline setting. At some point, they have progression. Michael, what are you going to do?

Michael A. Morse, MD, FACP, MHS: Thank you for picking on me. The simple answer is, we don’t know. We have to do something for those people. For somebody who has maintained their performance status and we are able to manage the toxicities of these drugs, it’s fair to say we should start them on something and, if they progress, move on to the next drug.

You could make the argument that cabozantinib was tested in patients as either second- or third-line therapy, and approximately 7% or so of the patients who were on the CELESTIAL trial had received a prior immunotherapy. I don’t think we have that data with regorafenib, mainly because of when it was studied.

Richard S. Finn, MD: It is also a purely post-sorafenib study.

Michael A. Morse, MD, FACP, MHS: Correct. You could make those academic arguments about what we do when we don’t have data. Cabozantinib was studied in a slightly broader patient population, without the requirement that, for example, a lot of people had more liver involvement, with portal vein involvement. And you could have bile duct involvement. But the reality is, both drugs—regorafenib and cabozantinib—have activity. And so I offer both options to people.

The main point that I’m trying to make here is that it is important that we manage those toxicities so people can get the benefit of the drug. And if they progress, hopefully they’ll be a candidate for third-line therapy.

Richard S. Finn, MD: With atezolizumab-bevacizumab leapfrogging to the frontline setting, it sounds as though you go to 1 of the second-line drugs—regorafenib or cabozantinib—when patients progress. Do you see lenalidomide or sorafenib being used in that setting?

Michael A. Morse, MD, FACP, MHS: That would be very reasonable. As you know, the NCCN [National Comprehensive Cancer Network] Guidelines do include sorafenib in that scenario. They are all reasonable options. Ideally, we’ll have some data in the future, although I’m not sure we ever will, looking at what that proper sequence should look like.

I suppose you could even extend that to changing the immunotherapy component or doubling up on the immunotherapy component. Those are legitimate questions, even where ramucirumab fits in a patient who’s already had bevacizumab.

Richard S. Finn, MD: Catherine, what is your take on this? It’s expert opinion, so…

Catherine Frenette, MD: It’s tough, and you’re right. There are no data, and it’s really anybody’s best guess at this point. In general, we would lean toward the second-line options: cabozantinib, as Michael had said, or regorafenib, potentially. I probably would not go to ramucirumab, even in patients with an elevated AFP. That said, I’ve used lenvatinib and sorafenib in the second-line setting. It’s very muddy waters at this point, so it can be a little difficult to make that decision.

Richard S. Finn, MD: Yeah. I was part of a review that we published early this year. Many of us thought you would go to the frontline TKI because of the choices we talked about before. Then we would look at regorafenib or cabozantinib, which would become third-line therapy because they’ve been studied after a prior TKI. Needless to say, we have made a lot of progress in liver cancer and need to adapt that data into the settings of progress we’ve made. We shouldn’t throw out all this data. We’re never going to repeat phase 3 studies just because the frontline choice came forward.

What we have proven from the phase 3 studies is that the drugs we have available are active antiliver cancer drugs. It’s important that we give patients the option to get these. That really brings up some clinical management questions.

First, we can’t wait until a patient has clinical progression anymore, right? When all we had was sorafenib, imaging became less important. Now that we have other drugs available in the second- and third-line settings, following patients with scans and documenting radiographic progression before they decompensate or have clinical progression is important, to give patients the benefit of these other drugs that appear to be active.

That also relates to something we spoke about earlier: transitioning patients, right? From intermediate to advanced, from locoregional treatment to systemic treatment, this needs to be done in a careful, appropriate, and thoughtful way, so we maximize the opportunity to get systemic drugs. I’m starting to see patients who have large tumors, who have less compensated liver disease, who get a response and their livers actually get better. Their liver function improves because they responded. This is a whole new era for us in liver cancer research.

The other thing, Michael, is that now we have ipilimumab-nivolumab approved in the second line, right? We saw an accelerated approval of CTLA4 plus PD-1. Is there a precedent to use that after prior progression on a PD-1 or PD-L1 inhibitor?

Michael A. Morse, MD, FACP, MHS: Certainly it’s a new concept in hepatocellular carcinoma [HCC]. We really don’t. If you look at some melanoma literature, there can be activity. It just points out the fact that we don’t really understand which patients are likely to benefit from the immunotherapy, and what the resistance mechanisms to the immunotherapy are in hepatocellular carcinoma. In a nonrandomized fashion, it does appear that there is more activity for anti–PD-1/anti–CTLA4 than single-agent anti–PD-1 therapy. Again, there were different cohorts of patients in CheckMate040, and we have data on durvalumab and tremelimumab as well.

But whether that warrants the use of those, as Catherine pointed out, at least with nivolumab and ipilimumab having toxicity issues—particularly with ipilimumab 3 mg/kg— we have to be very careful regarding which HCC patients we’re applying them.

Transcript edited for clarity.