Systemic Therapy in MHCC: Sorafenib vs Lenvatinib

Transcript: Ghassan K. Abou-Alfa, MD: The combination of systemic therapy plus local therapy has not been out already, as Katie said. If anything, a lot of work that happened with systemic therapy including sorafenib on multiple occasions that resulted in negative trials. Nonetheless, now there’s an attempt for probably looking into checkpoint inhibitors for that purpose. And if anything, interestingly, however, the move of trying to get the add-on of the local therapy, or rather the add-on of the systemic therapy to a local therapy for local treatment might not necessarily be true. And ironically, there was a report just not that long ago that came out of China that looked into adding the local therapy to the systemic therapy for systemic disease?

So as you can see, there’s quite a bit of debate in that regard. But more importantly, as we said before, it’s very important to make sure that you already have a multidisciplinary discussion to make sure that patients are served best.

This brings us to the important component of our discussion, which is systemic therapy. And I have to say, I’ll start with a joke like, you know, why the great job? We just had to only remember one drug for that long period of time, and now it’s really complex now. We have to worker harder. So, Katie, tell us even before sorafenib, what were we doing for HCC [hepatocellular carcinoma] patients?

Katie Kelley, MD: Before sorafenib there was really no systemic therapy agent that had shown a meaningful survival benefit in any randomized trial or other contexts. And so we historically would use drugs that we used in other cancers like doxorubicin [DOXO], the same drug we use in TACE [transarterial chemoembolization] now or DOXO liposomal variant thereof. And sometimes there are even harder chemotherapies to tolerate, but back to our conversation about the diseased liver—these were poorly tolerated—the HCC, or hematosarcoma that’s rather chemoresistant tumor type with respect to conventional cytotoxic chemotherapy. So we were combining toxicity with minimal efficacy to very little, to no gain I should say, and so prior to sorafenib the field was very limited for oncology to benefit the patient.

Ghassan K. Abou-Alfa, MD: And Amit, the oncologists come to you and say, “Hey, by the way, we have a new drug called sorafenib, what do you think?”

Amit Singal, MD: You know the SHARP Trial basically changed the landscape. This came out a decade ago, and as Katie was saying before, we had nothing. And then we had a therapeutic option. I remember when the drug came out all of us were like: “This is great, we have an option. It’s the first step, we’re going to have something even better 2 years from now.”

And until recently that’s all we had for nearly 9 years. And so it really just shows you how hard of a cancer this is to treat. The nice thing is that over the last 2 years we’ve made even more progress, many more drugs have come to market. But really I think sorafenib changed the entire way that we think about advanced disease.

Ghassan K. Abou-Alfa, MD: Fair enough. I think it brought a lot of questions rather than only answers. So, Farshid, not that long ago we heared about another drug called lenvatinib. Tell us more.

Farshid Dayyani, MD: So lenvatinib is a tyrosine kinase inhibitor [TKI] that targets VEGF [vascular endothelial growth factor] receptor 1, 2, 3, FGFR [fibroblast growth factor receptor] 1,2,3 and some others like KIT and PDGFR [platelet-derived growth factor receptor]. And as was already mentioned, for 10 years, 4 large randomized trials failed to actually show superiority or noninferiority to sorafenib until the REFLEX Trial was performed, a large randomized phase III trial, noninferiority design against sorafenib in the first-line setting.

Ghassan K. Abou-Alfa, MD: Teach us a little about noninferiority, what does that mean?

Farshid Dayyani, MD: So the difference between noninferiority and superiority is a) you need more patients and b) you need to define how much worse the drug can be based on your confidence interval for me to still accept it as equal. Then you can focus on other endpoints such as response rate, progress-free survival [PFS], tolerability, etcetera, when your primary endpoint is not inferior. Then you can try to differentiate drugs based on other endpoints rather than the primary endpoints.

Ghassan K. Abou-Alfa, MD: So if I hear you correctly, in other words, if you are having a non-inferiority study, if the Kaplan-Meier curve really looks like they are hugging each other, that’s a positive study.

Farshid Dayyani, MD: That’s actually what you want to see, exactly.

Ghassan K. Abou-Alfa, MD: Tell us what happened in the lenvatinib study.

Farshid Dayyani, MD: So in the lenvatinib study the primary endpoint overall survival [OS] was met. Overall survival with lenvatinib was about 13.2 versus 12 something. Sorafenib actually performed much better than anticipated. So clearly the hazard ratio was very close to 1, and that was the primary endpoint that was met, there was no difference in overall survival. If you look at the secondary endpoint progression-free survival, response by RECIST, unmodified RECIST, time on treatment, time to treatment failure, those were all favoring lenvatinib in that trials in terms of toxicities.

Ghassan K. Abou-Alfa, MD: Well, hold on with that, that’s a lot to absorb, my friend. I’ll tell you, that’s incredible. Like after 10 years we have another study with an improvement in survival by passing the 1 year threshold. It was a design that actually Farshid explained to us that is a noninferiority design. And understandably we use this kind of design in oncology in general, and there are certain specific purposes for that. But I’ll go back to the other endpoints that Farshid mentioned, and I’ll ask you Katie. Tell us a little bit more about the progression-free survival and the response rate. What do they mean and how different were they in that study?

Katie Kelley, MD: Right. The progression-free survival and the response rate were both measured locally, so it was an open-label trial but they were confirmed centrally on the back end of the study, meaning after the trial was done, blinded radiologists confirmed that the site radiologists were accurate and consistent with the central review. The progression-free survival was substantially longer for lenvatinib than sorafenib, as was the overall response rate by using the modified RECIST tool which instead of looking at just the total size of the tumor, really focuses on the enhancing part of the tumor, meaning the arterial blood flow to the tumor. Those criteria perhaps are most validated in liver-directed therapy. They really haven’t been studied as much in metastatic disease or extrahepatic disease as a caveat to using modified RECIST for this response endpoint. But, nonetheless, those 2 secondary endpoints did show superiority, preplanned secondary analyses for the study. Again, the caveat being an open-label design which even though central review is similar, the decisions about patient treatment are made at the local site level.

Transcript Edited for Clarity