Ghassan K. Abou-Alfa, MD: Dr. Vogel, what impressed you about this study other than noninferiority, equal survival advantage with some trend towards more superiority in regard to the lenvatinib? But what else was really impressive to you from that study?
Arndt Vogel, MD: So, I think the secondary endpoints were also very impressive. Not only that it’s a positive study, it’s also that the response rate—which was clearly higher than with sorafenib, specifically when we look at the mRECIST response rate—goes up to 40%, which we have never seen before.
Ghassan K. Abou-Alfa, MD: Forty percent?
Arndt Vogel, MD: Yes, in systemic therapy. And even now, we’re just getting close to the response rate we see with TACE and Y-90, so it’s really impressive. Of course, PFS is also significantly longer, 3.8 to 7.4 months.
Ghassan K. Abou-Alfa, MD: Almost double
Arndt Vogel, MD: Almost doubled, right. TTP, or time to progression, has almost tripled. So, the secondary endpoint, they indicated the drug is more active compared with sorafenib. But we also, of course, have to keep in mind that this did not really directly translate into a significantly better overall survival. So, I think we have to be careful that we don’t overestimate the secondary endpoints. On the other hand, when we look at the activity of a drug, I think we also can’t ignore them. What Dr. Kudo just said, it’s really amazing how many patients have been treated in Japan and that they see this early decrease in AFP and necrosis after 2 weeks. This is kind of an indication that this is really an active drug. So, I think these secondary endpoints are also something we need to keep in mind when we decide on which treatment we choose for our patients.
Ghassan K. Abou-Alfa, MD: I would say yes, you’re right, they’re important. But I cannot really do anything but say whoa when it comes to the response rate: 40.9% in regard to modified RECIST on the drug, that’s really impressive. That’s good that you heard this. Probably all of us are kind of referring one way or the other that we’re very impressed with regard to the secondary endpoints, which really showed impressive improvement in outcomes. What did not make the study a superior study? In other words, despite the fact the design was for noninferiority, why wouldn’t it even meet a superiority cutoff in that study? What’s your explanation?
Masatoshi Kudo, MD, PhD: There are 2 reasons, I think. One reason, the post-trial treatment. Post-progression survival is too long because of the post-trial treatment like systemic therapy. It is too long, so the hazard ratio was diluted because of that treatment. Another thing is AFP imbalance. But covariate analysis clearly showed the AFP was imbalanced, favoring sorafenib. That was collected by covariate analysis. The significant difference was demonstrated. So, that means if it’s included in the stratification factor, there might be superior results. So, I think those 2 are the main reasons that the REFLECT trial did not show superiority.
Ghassan K. Abou-Alfa, MD: This is very, very important. I definitely know that you paid attention to every word Dr. Kudo has mentioned, because this is really critical that the study, of course, because it’s not superior, we cannot isolate it from what else patients should have been or could have been in regard to therapy. And, as such, because we don’t have control to what happened after the study, this could have very much influenced that noninferiority, really not to show the superiority per se. But there are other components, as we just heard, in regard to the AFP level, which was actually in favor of the sorafenib arm that really made it a noninferior study. But, nonetheless, it does not really discredit the important outcomes that we spoke about with Dr. Vogel in regard to the improvement in PFS, TTP, and the response rate. I would like to touch on one more point in regard to lenvatinib, and we’ll hear it from the expert. Masatoshi, tell us a little bit more. You mentioned in the beginning as you introduced the concept of lenvatinib, but our experience has been the drug is rather very well tolerated. What’s your experience in Japan and what’s your view on the adverse events?
Masatoshi Kudo, MD, PhD: Adverse events, or AE, profile is different from sorafenib. So, subjective AEs like hand-foot-skin syndrome or diarrhea are very little or less. And other AE profiles like hypertension, proteinuria, or hypothyroidism are more frequent. But the patients do not feel those kinds of AEs, so of course, physicians have to monitor, and we can manage easily. The AE incidence is similar, but subjective AEs are much less in the lenvatinib arm. So, it’s very easy to manage.
Ghassan K. Abou-Alfa, MD: To manage, yes. We’ll see how it goes. Rich, what do you think? The FDA will approve it?
Richard S. Finn, MD: Yes, it met its endpoint. There’s no reason it should not be approved, and I think at the end of the day, we’ve been asking for another option for frontline therapy for 10 years, and now we have one. It does not mean it automatically replaces sorafenib. The overall endpoint was equivalent, but it’s good to have another option for patients. I think that’s very important, and there are some characteristics that favor one drug over the other. You mentioned hand-foot syndrome, toxicity. We see with hepatitis C, maybe sorafenib, those patients do better and that might have been another imbalance that caused some reason that it wasn’t overtly positive, and that there were more hepatitis C patients in the sorafenib arm. And we have seen in other studies that hepatitis C might be a group of patients who do better with sorafenib. So, it should be approved based on tolerability and efficacy.
Ghassan K. Abou-Alfa, MD: I totally agree with you. I would say probably the expectation is that it will be approved in no time.
Transcript Edited for ClarityBrought to you in part by Eisai