Oliver Waidmann, MD: In Study 304, the key finding was that lenvatinib wasn’t inferior to sorafenib. This is the key finding, and it was statistically significant. The overall survival in the patients who received lenvatinib was 13 months, and the overall survival in patients who received sorafenib was 12 months, so there was no big difference in the trial. We also saw an improvement in overall survival in the sorafenib patients. But I think it’s not really the most important finding. I think the interesting finding was that the overall response, time to progression, and also the progression-free survival in lenvatinib were much longer. It was about 30% longer compared to sorafenib, and I think this is the big issue and the big benefit of this drug.

Arndt Vogel, MD: Here at ASCO, Study 304 has been reported, which compared the efficacy of lenvatinib to sorafenib. The study design was a noninferiority design, so the idea was to show that lenvatinib is as good as sorafenib. And secondary endpoints were PFS, TTP (or time to progression), and response rate. This was, and this is, really good news—a positive trial, the first positive trial in the past 10 years. Numerically, the overall survival was better with lenvatinib, 13.7 months, compared to 12.3 months with sorafenib. With these numbers, it was not shown that lenvatinib is superior in terms of overall survival compared with sorafenib. But it was a positive trial, so noninferiority was shown.

Interestingly, all the secondary endpoints—such as PFS, TTP, and response rate—were not only statistically significantly improved, but I think they were also clinically, meaningfully improved. Specifically, time to progression, for example, was increased from 3.7 months with sorafenib to more than 8 months with lenvatinib, so clearly this is a significant improvement. And also, the response rate was significantly improved from 6% or 8% to 24% with lenvatinib. So, we have clearly a very active drug.

Overall, this is very good news. But on the other hand, there is also some concern because overall survival was not significantly improved, and one could ask, “Why do we need another drug if overall survival is not improved?” This is not an easy question to answer, and I think there are, so far, no good answers to the question of why the overall survival was not significantly improved. I think when we look at the trial, there were some imbalances that were in favor of sorafenib. So, there were more patients who had a low AFP level. There were more patients in the sorafenib group who had hepatitis C infection, and we have learned in the past that hepatitis C infection really derives a good benefit from sorafenib.

AFP is clearly a prognostic marker, and it was a prognostic marker in this trial. Patients with a lower AFP, smaller than 200 nanograms/mL, had a much better median overall survival, reaching almost 19 months with lenvatinib compared with a median survival only around 10 months for patients with an AFP level that was greater than 200 ng/mL. So, AFP is a prognostic marker, and there were more patients with a lower AFP in the sorafenib group, indicating that there were probably clinically important imbalances. What they have done in the trial is correct the overall survival data and adjust the overall survival for the AFP levels. And with this adjustment, the overall survival was significantly improved. If the trial had been negative, I think it’s not a good argument to do post hoc analyses, but this was a positive trial. And I think in this situation, it’s fair to do an adjustment for an established negative prognostic marker.

But still, another point that also needs to be discussed is the side effect profiles. And, numerically, both drugs are active drugs and they both have a lot of side effects. So, if you look just at the numbers, most patients develop side effects and the numbers are evenly distributed between both drugs. If you look at the profile of side effects, there are some differences. Some of them are just because they are tyrosine kinase inhibitors. Fatigue and decreased appetite, we can find with both drugs. But specifically with sorafenib, we find a lot of diarrhea and also hand-foot skin reactions.

In contrast with lenvatinib, we have more hypertension and proteinuria. But these are side effects that the patients do not really feel and that do not affect their quality of life. And with a higher incidence of diarrhea and hand-foot skin reaction, when we look at the quality-of-life data in this trial, they were in favor of lenvatinib, specifically when we look at body imaging or if we look at the diarrhea and pain. So, the side effect profile is numerically similar, but there are differences in what kind of side effect occurs. And this was also reflected in the quality-of-life assessment that has been done in the trial. Overall, I think it’s good and it’s a positive trial. It’s a new drug. It’s a different drug from sorafenib, and I think even if the overall survival is not significantly improved, because all of what I have said before, it’s a drug that we should use in HCC.

Transcript Edited for Clarity

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