Evolving Treatment Paradigms for Metastatic Liver Cancer - Episode 5

IMbrave150 Phase III Trial for MHCC


Ghassan K. Abou-Alfa, MD, MBA: There is a big elephant in the room, and already indirectly one will talk about the local therapies. We mentioned 2 drugs—sorafenib, which we all know has been the standard of care for a long time—and we talked also about lenvatinib. And there is no advancement. Before we get to do advance, tell us, Catherine—lenvatinib, what is it?

Catherine T. Frenette, MD: Lenvatinib is a tyrosine kinase inhibitor [TKI], a multikinase inhibitor, similar to sorafenib. It has a little more VEGF activity. And it was studied in the REFLECT trial, in which they looked at lenvatinib compared with sorafenib as a noninferiority study. Meaning they wanted to show noninferiority. And the study was a positive study that showed that lenvatinib was noninferior in terms of overall survival.

Interestingly, in the study the secondary end points of response rate were actually higher in the lenvatinib. We do see a bit more response rate with lenvatinib. Because it also hit the different TKIs, we do see a little different adverse effects where there’s more hypertension with lenvatinib and less of the hand-foot-skin reaction than we see with sorafenib. There is a little bit of a difference between the therapies in that way as well.

Ghassan K. Abou-Alfa, MD, MBA: That’s lenvatinib, and as we heard—it’s was in a noninferiority study, but nonetheless great in the improvement and in progression-free survival and response rate. By all means, it’s a standard. But then, Anthony, for the last 3 days, every day I heard ATEZO-BEV [atezolizumab-bevacizumab] almost every 5 minutes. What is that?

Anthony B. El-Khoueiry, MD: This is based on the emerging results, and now we have a phase III study called IMbrave150. This combination of atezolizumab and bevacizumab is based on the concept of concurrent inhibition of PD-1 [programmed cell death protein death 1] from the immune therapy perspective, and anti-VEGF therapy. This is based on good scientific evidence. The anti-VEGF therapy not only changes the angiogenic milieu in the tumor but also has immunomodulatory affects, especially on myeloid, like the pressor cells, macrophage balance, etc. Anti-VEGF therapy may actually synergize with anti—PD-1 therapy.

There are many combinations being studied in this space. But you asked about atezolizumab and bevacizumab because it has the most mature data at this point. I guess from that end we now have a phase III study that compares atezolizumab plus bevacizumab with sorafenib in the first line. So previously untreated patients. All Child-Pugh score class A.

In this study, reported not long ago at ESMO [European Society for Medical Oncology] Asia Congress 2019 and showed again at this meeting, the Gastrointestinal Cancers Symposium, there was a significant improvement in overall survival with this combination with a hazard ratio of 0.58. There was a 42% reduction in the risk of death with atezolizumab-bevacizumab compared with sorafenib.

Similarly, there was a statistically significant improvement in progression-free survival. We’re talking about 7 months with atezolizumab-bevacizumab compared with close to 4 or so months with sorafenib.

So all end points appear to be positive. The median overall survival has not been reached. The median follow-up on this study is a bit short, around 8 months. Nonetheless, this is a positive trial. It’s the first positive trial in first line as a superiority study compared with sorafenib. And it’s likely to change the standard of care in the near future.

Ghassan K. Abou-Alfa, MD, MBA: I totally agree with you. Even though the data for the survival are not totally out yet. There are data but people are doing extremely well on ATEZO-BEV [atezolizumab-bevacizumab] and continue to linger in time. We didn’t cross the median, but it doesn’t mean that’s what’s going to be very good. Along that line, Ahmed—Monday, you have clinic, are you going to give ATEZO-BEV [atezolizumab-bevacizumab]?

Ahmed Kaseb, MD: In general, we also have to weigh the risk-benefit ratio, in terms of the adverse-effects record of each combination, and personalize your treatment plan.

Ghassan K. Abou-Alfa, MD, MBA: This is a patient who’s like a patient with Child-Pugh A5: perfect. Will you give ATEZO-BEV [atezolizumab-bevacizumab]?

Ahmed Kaseb, MD: It depends on the data, of course. If it’s very compelling. If you don’t have a clinical trial option that could offer this.

Ghassan K. Abou-Alfa, MD, MBA: There’s no clinical trial.

Ahmed Kaseb, MD: It could be an option in patients who could manage and tolerate it, because it’s a positive study. It’s under review. We expect it to be the new standard of care soon. It can also be very important for us as clinicians. In future clinical trials, this is going to be the new control arm. Here you’re raising the bar in terms of survival and response rates and so on. Also, for combination strategies that we’ve been talking about—combining systemic and local therapy—this could also offer a very nice advantage, because it’s both either IV [intravenous] and tolerable. Especially in patients with metastatic disease, because the cause of death is usually liver failure from liver tumor progression. It’s really going to help all of us in the field move faster to the next level.

Ghassan K. Abou-Alfa, MD, MBA: Do you notice that I thought to really squeeze the situation as best as possible because I always respect the opinion of Dr Kaseb. As a scientist, you will definitely look at the data and analyze it and put it in perspective.

Interestingly, the 2 drugs are available, and if anything we have seen experience or the patients are getting the atezolizumab in the practice. By all means, even while we’re waiting for the maturation of disease, we are already seeing it in practice. Of course, as Anthony summarized, the survival outcome and progression-free survival outcomes are really quite impressive, not to mention the response rate.

Transcript Edited for Clarity