Clinical Trials of Lenvatinib Combination Therapy

EP: 1.An Overview of Hepatocellular Carcinoma

EP: 2.Defining Unresectable and Advanced HCC

EP: 3.The REFLECT Study of Lenvatinib for Unresectable HCC

EP: 4.Lenvatinib Combination Therapy for Treatment of HCC

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EP: 5.Clinical Trials of Lenvatinib Combination Therapy

EP: 6.Future Directions in Systemic Treatment of HCC

Richard S. Finn, MD: While the landscape has changed significantly in the past few years, the activity of AtezoBev is practice changing. But there will still be roughly, I think, many of the estimates around 15% of patients who will not qualify for that because of some of the issues we just raised. And for them, again, the TKIs, lenvatinib based on reflect studies, sorafenib based on the Sharp study are potential treatment options. Now, lenvatinib was approved in 2018. And over the past year, including at the recent ASCO meeting and ASCO GI this year, we've started to see some real-world data coming out of academic groups, looking at how well the lenvatinib data has held up in the real world compared with reflect. So, 2 studies have been presented this year. One from my colleague and friend from UT Southwestern and another study coming from Canada. And both of these studies seem to recapitulate the findings of reflect in regard to response disease and disease control rates with lenvatinib in the real-world setting. These kinds of data are always reassuring. I think given phase 3 studies always select by design, a group of patients based on strict inclusion and exclusion criteria. And so, taken together for those patients who won't get AtezoBev, these data are telling us that lenvatinib is a reasonable option for that subgroup. Certainly, patients who do not qualify for AtezoBev in the frontline setting and start with lenvatinib, as their frontline option. Certainly, a progression single-agent I/O might be an option, assuming that they are candidates for I/O. And again, the data that has supported that has been response rates of around 15% to 20% repeatedly, with single-agent nivolumab and pembrolizumab. Now, based on data with single-agent I/O, there has been interesting in obviously combining I/O regimens.

But we've seen early data now, with lenvatinib in combination with pembrolizumab that looked very promising. We had published last year in JCO, a single-arm combination study of lenvatinib and pembrolizumab in the front-line setting that was completed before the approval of AtezoBev, that showed objective response rates of 36% by resist criteria. And again, this number is not too dissimilar from what we saw, in the single arm 1B study of AtezoBev. And this has been the basis for the LEAP-002 study, which is a front-line study of LenPembro versus lenvatinib, in the front-line setting. And interestingly, the regimen of LenPembro is very well tolerated. Most of the side effects we see are similar to those that we see with single agent lenvatinib. Certainly, there are patients who have immune-related adverse events, but they are really no higher than what was seen in single-agent I/O studies. And while we eagerly await the results of LEAP-OO2, there were some studies at ASCO this year that evaluated the activity of this regimen, in various settings. There was a study from Hong Kong that looked at this combination or more generically TKIs, after prior I/O and show that response rates were maintained after prior I/O therapy when using either single-agent TKIs or even TKI I/O combinations. One of the things we don't know, is all the group of patients that respond to AtezoBev, the same group of patients that are responding to LenPembro, given that lenvatinib is a multikinase inhibitor and hits not only VEGF receptor but other kinases. Does that provide a different strategy for not only upfront treatment, but even in a second-line setting? Will there be an opportunity for TKI I/O, after progression on AtezoBev? We saw an interesting study at ASCO GI looking at patients who got lenvatinib in combination with a checkpoint inhibitor and looked at changes in AFP or Pikva.

And they observed that patients who had an early response in either of these tumor markers, Alpha-Fetoprotein or Pikva, a protein induced by vitamin K abscess. But patients who had decreases in these early on, that was associated with an objective response by resist. And again, these are things that tell us who responds upfront. These aren't predictive markers to select treatment, but these are interesting correlates that tell us that a decreasing tumor marker early on, may be associated with an objective response. That's not to say that if you do not have an early response in tumor marker, or you don't have elevated tumor marker at baseline, that you don't respond, it's all a matter of proportions of responders.

This transcript has been edited for clarity.