Richard S. Finn, MD: This 2017 ASCO Annual Meeting has been a very exciting meeting—not only at ASCO, but even in the past year—as we’ve heard about the regorafenib data. Arndt, you were one of the investigators on the study with lenvatinib versus sorafenib, the first positive study in first-line liver cancer for a decade. Can you give us the take-home message from that study?
Arndt Vogel, MD, PhD: Yes. This is really great news, and I think this is clearly a positive study. We have already discussed the difference between superiority trials and noninferiority trials and what is a positive trial and what is a negative trial. And here, we clearly have a positive trial. This is very good news. When we look at the data that have been presented, and we have just recently seen, the survival with lenvatinib is numerically better than with sorafenib, but it did not reach superiority. So, this is one point we need to keep in mind.
Then, when we look at the secondary endpoints, I think they were not only statistically significantly improved, but they were also clinically meaningfully improved. There were different tests; specifically, progression-free survival, time to tumor progression (TTP), and response rate. When you look at TTP with sorafenib, as expected, TTP was 3.7 months. In lenvatinib, it was more than 8 months. That’s a clear signal of stronger activity. And also, when we look at response rate, we have an increase from 8% to 24%.
Richard S. Finn, MD: By modified RECIST criteria?
Arndt Vogel, MD, PhD: By modified RECIST criteria.
Richard S. Finn, MD: Not the traditional RECIST criteria that looks at shrinkage of tumor, but decreases in the amount of enhancement?
Arndt Vogel, MD, PhD: Right. What we also have to say, of course, is that these are secondary endpoints. You could argue if overall survival has not improved, what do these, the secondary endpoints, mean? Therefore, I think we really need to critically look at these data.
What we have already seen, and what has been reported, is that there are some imbalances. For example, there were more patients with hepatitis C that received sorafenib, and we know that patients with hepatitis C respond very well to sorafenib. The median overall survival of these patients in the trial was 14 months, which was very good.
Another point, or another imbalance, which was seen, was the AFP level. This has been reported in the first presentation. In the group of patients treated with sorafenib, more patients with a lower AFP were included. In contrast, more patients with a higher AFP were treated with lenvatinib.
When we look at these different subgroups, we can clearly see that—and this has been confirmed with this trial—AFP is a prognostic marker. With lenvatinib, a patient with a lower AFP has a median overall survival of almost 20 months, which is really good. In contrast, patients with a higher AFP have a median overall survival of around 10 months. In both groups, median overall survival was longer with lenvatinib compared to sorafenib. So, when you do an adjustment for AFP levels, you do get a significant improvement in overall survival. But this, again, of course, is only a post hoc analysis, and it does not really make it to a more positive trial as it already is.
Richard S. Finn, MD: At the end of the day—and, again, we only saw the data yesterday—we’ll wait for the publication. They seem to be equivalent. Are there any toxicity differences?
Arndt Vogel, MD, PhD: If you look, numerically, at toxicity, they appear to be very similar. If you just look at the numbers of side effects that occur, we have the typical side effect profile that we would expect from sorafenib—with diarrhea, hand-foot-skin reactions, fatigue.
In contrast, with lenvatinib—and this, I think, is also expected—we see more hypertension and proteinuria. In terms of how this affects quality of life—I think quality of life is really important—we have to take the tools that are available. If you look at them, we see that, in general, the numbers are very equal in terms of quality of life for sorafenib and lenvatinib. There are some subgroups that are in favor of lenvatinib, which goes hand-in-hand with a higher incidence of diarrhea, for example, which we see in the side effects.
Richard S. Finn, MD: I guess we’ll have to see how these data filter in as we learn more from the study.
Jordi Bruix, MD: Can you comment on the difference in terms of an open-label study versus a blinded trial?
Richard S. Finn, MD: For the audience, this was not a blinded study. This was open-label.
Arndt Vogel, MD, PhD: Yes. Of course, you could argue on the 2 ways of how this could affect it. And you could argue, of course, that in patients who are treated with lenvatinib—and currently, there are a lot of patients treated with sorafenib—patients and physicians knew that they had received sorafenib. And, they were, of course, candidates for subsequent clinical trials. But all of these trials in the second-line were positive, so they might not have derived any benefit from second-line trials.
They might have been taken off sorafenib too early, which would be a mistake in this case. But if you look at the reasons for discontinuation of sorafenib in this trial, we do see that more patients have been treated until radiological progression with sorafenib compared to lenvatinib. So, I do not think that more patients have been taken off sorafenib too early. The numbers match very well to other data we have seen before. And on the other hand—of course, some of the patients have been treated with regorafenib that have received sorafenib—they might have derived a benefit in later lines, which also might have contributed to the longer survival in the sorafenib arm.
Richard S. Finn, MD: We’ll have to, again, dissect these data as they become more widely available.
Transcript Edited for Clarity