Case 2: Choosing the Right Treatment Option



Ghassan Abou-Alfa, MD, MBA:You mentioned to us 7 drugs already between yourself and Amit. How can I choose?

Farshid Dayyani, MD:There are different ways to do that obviously, and the more painful way is for every single patient to go back and say, “OK, would that patient fit the eligibility criteria for their respective trial? Did the patient benefit for many, many months on sorafenib?” Or you try to choose the drug that has the least restriction eligibility, and you’re not going to be wrong. Some people might say switching the mechanism of action might be a way to do this from an anti-VEGF tyrosine kinase inhibitor [TKI] to an immuno-oncology [I/O] agent. But I think the data will lead us.

We have 2 negative randomized phase III trials with single-agent I/O versus placebo or sorafenib, as you showed. But we have 3 positive anti-VEGF second-line trials. I don’t think the hypothesis is that switching mechanisms of action necessarily will be a guiding principle. I look at the patient, look at the underlying liver function, and look at the performance status. What was the prior treatment? What were the toxicities? Together with the patient we’ll make the decision. Most of the time, if I need disease control rather than having the luxury of time to wait, I’ll go with the drug that gives me high disease control rate such as cabozantinib—for example, with a 67% range of disease control, whereas initially with an I/O that might drop to 30% or so. So that becomes another way to look at this.

Ghassan Abou-Alfa, MD, MBA:I might challenge you here, but by all means, I totally agree that we might have different perceptions in regard to the disease. If anything, especially if I bring in what Riad just mentioned, I’m available. If things are stable, I might really revisit things 1 way or the other. As such, I probably agree with you that response is key.

At the same time, I would like to really revisit the 2 phase III trials in regard to the pembrolizumab versus placebo, and of course the nivolumab versus sorafenib. Yes, they were negative. At the same time, it was not as if they were disastrous. They did not show the primary end point, and I still stand by that the anti—PD-1 [programmed cell death protein 1] by itself does not work on the disease. At the same time, the response is very critical over here as it was already seen in the phase II data that we have. As such, I would like to go back to Amit and say, do you think anything was wrong here? For example, for our patients here who got lenvatinib, progressed on lenvatinib, we’ll give them pembrolizumab.

Amit Singal, MD:I don’t think there’s anything wrong with it. I agree with you that at the end of the day, when you take a look at the KEYNOTE trial, it’s a negative trial. But when you then break down the data and you take a look at this, there was a benefit there. It’s just that it wasn’t statistically significant because there were 2 coprimary outcomes, and they looked at the data early.

At the end of the day, when you take a look at the absolute survival, there is a survival difference, and there are differences in terms of the responses. I do think that I/O agents play a role in the management of HCC [hepatocellular carcinoma]. I don’t think it’s wrong to use it in the second line, particularly in somebody who progresses on lenvatinib. Farshid brought up points of how that patient does on lenvatinib. If somebody, for example, doesn’t tolerate TKIs well in the first-line setting, I’m much more likely to use immunotherapy in the second line. If they go through it quickly, if they basically have disease progression in 3 months, then I’m much more likely to use a checkpoint inhibitor in the second line.

I think they play a role. I just don’t think there’s 1 drug that works for everyone. I think that right now, it would be nice if we had something that would make us smart in terms of choosing. It would be nice if we can actually have molecular pathways that show that if your tumor has this pattern, we would use this drug. We don’t have that right now, so we have to use clinical characteristics that got patients into the trial or these other clinical factors, like how quickly you progress on the therapy and drug tolerance.

Ghassan Abou-Alfa, MD, MBA:I totally agree. If anything, at the end of the day the anti—PD-1 checkpoint inhibitors in the phase II trials did not really show improvement in survival. But the response data definitely are there and available, and they are already approved for that purpose. Nonetheless, we’ll see that our colleagues have more cases to discuss in our tumor board. But if anything, the combination of the checkpoint inhibitors plus TKIs, or even combination of checkpoint inhibitors plus checkpoint inhibitors, is really nowadays a very hot subject. The idea is that if an anti–PD-1 by itself cannot do it—and please do understand that an anti–PD-1 in HCC is not like an anti–PD-1 in lung cancer or in melanoma. If anything, a combination of anti–PD-L1 [programmed death-ligand 1] plus anti-CTLA4 or an anti–PD-1 plus a tyrosine kinase inhibitor or antiangiogenic would make it. We just have to wait for the data. I’m sure we’ll have more cases to discuss all those combinations that are coming, for which we are eagerly waiting for the results.

Transcript edited for clarity.

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