Upfront Lenvatinib in Unresectable HCC

Jul 30, 2018


Ghassan K. Abou-Alfa, MD: We spoke quite a bit about locally advanced disease and the value of local therapies. By all means, we are extremely grateful to all of our colleagues in interventional radiology (IR), in regard to all of the interventions that they can help patients with in regard to chemoembolization, bland embolization, and radioembolization. There’s quite a bit of important perspective in that regard. What’s fascinating, and this is what we are very proud of, is that we are really hand-in-hand with IR at the moment—trying to evolve toward how we can make it better. We just discussed the combinations with different therapies. For example, we discussed the use of biologic therapy—sorafenib. This study was negative. At the moment, we are looking at checkpoint inhibitors. I would not be surprised that, ultimately, we will see an antiangiogenic, something like sorafenib or the like, plus a checkpoint inhibitor and embolization. So, again, 3 therapies combined rather than a doublet, per se.

We’ll wait until those days happen, but, of course, it’s good to go back to that multidisciplinary team. You can gain the assets, learn from the value of what interventional radiology can really contribute, and can help our patients with hepatocellular carcinoma. That said, let’s really get to the meat of the matter. Most of the data is in regard to systemic therapy.

We know and understand that the standard of care that we’re all familiar with, that we all have been practicing with, is sorafenib. This was based on data that were published back in 2007 regarding sorafenib versus placebo. There was a clear survival advantage for patients who used sorafenib. This became the standard of care. We kind of had a hiatus of almost 10 years. No other data have shown positive, despite really incredible positive efforts that have been done with systemic therapy. And then, out of nowhere, we hear about a drug called lenvatinib. What’s the story there? Ruth, what’s lenvatinib?

A. Ruth He, MD, PhD: Lenvatinib is another TKI.

Ghassan K. Abou-Alfa, MD: A tyrosine kinase inhibitor.

A. Ruth He, MD, PhD: Yes. It has been approved in other cancers. The REFLECT study evaluated lenvatinib versus sorafenib in the frontline setting. It’s a noninferiority study.

Ghassan K. Abou-Alfa, MD: Let’s hold on for a second. This is very important. Lenvatinib is a TKI, has value, and has already been proven as functional in different diseases. And out of nowhere, as Ruth is saying, a certain trial occurred in which patients were randomized to lenvatinib against sorafenib with a noninferiority design. Mark, what’s noninferiority here?

Mark W. Karwal, MD: It’s a statistical concept. It’s the endpoint. Don’t confuse it. You can design your trial to show superiority, or noninferiority, or both. It was designed to show noninferiority, and it was a positive trial. It showed noninferiority.

Ghassan K. Abou-Alfa, MD: Absolutely. It was very important that this was in the statistical design. There was a clear understanding of, “We are not necessarily trying to show that we are better, but we will take it, if we are really as good as sorafenib, as the statistical design for the study.” As such, it has to be read from that perspective. We can’t say, “Oh, but it didn’t…” It is actually a positive study. As we just heard from Ruth, there was equality, regarding the survival between the 2 drugs.

Interestingly, in addition to that, there has been, however, a quite intriguing point regarding the progression-free survival. It almost doubled. In addition to that, there was an overwhelming impressive response rate of 40.7% by what we call modified RECIST. Before we go to that data, let’s learn what modified RECIST is. Amit, maybe you can tell us?

Amit Singal, MD: The traditional RECIST criteria basically measure the diameter of the tumor. But we’ve already talked about the importance of arterial enhancement for HCC. And so, modified RECIST basically takes the diameter of that arterially enhanced component. This is important. Sometimes, when you have a response with HCC, the diameter doesn’t change but the proportion that continues to have arterial enhancement will decrease. So, RECIST and modified RECIST will actually give you different numbers in terms of response rates. And so, modified RECIST is thought to be more accurate, in terms of the viable component of that HCC.

Ghassan K. Abou-Alfa, MD: I admit that the modified RECIST assessment is relatively new. I didn’t really contribute at all. I was not really involved in modified RECIST. But, interestingly, on the first phase II trial of sorafenib, on a Friday afternoon, I went to look at a CAT scan. We always recommend, to all fellows, to look at the CAT scan. This is what we always say. I looked at the CAT scan and I saw some change in intensity, exactly as Amit is saying. So, what did I do? I didn’t know what I was looking at, so I picked up the phone and spoke with the radiologist, Larry Schwartz. Larry and I discussed tumor necrosis. The question was, how could we quantify it? And so, we built a model that would look at the size or volume of the tumors, to look at the intensity change that we might see on the CAT scans. Then, it was carried forward. We’re still analyzing it, from that perspective, and we are adding more perspective to this related to certain biologies.

But, nonetheless, I give credit. Riccardo Lencioni carried on with that. Of course, it’s not like any secret observation that we saw. People could have seen it with any other TKI. If anything, it was carried with the modified RECIST component that, interestingly, was first looked at in a retrospective fashion. That’s really why we’re not necessarily sold on this. Retrospectively, you can read it any way you want. But, interestingly, and ultimately, they started doing it in a prospective fashion in clinical trials, like the lenvatinib study. It’s really impressive. There is a 40.7% response rate. This really beats anything that we’re aware of, in regard to the use of TKIs or other therapy in HCC.

Transcript Edited for Clarity

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