Post Conference Perspectives: Immunotherapy Combinations for Unresectable HCC - Episode 2

IMbrave150 Phase III Design, Results, and Practical Implications


Ghassan K. Abou-Alfa, MD: I would say that we’re very happy to see the results of the IMbrave150 study, which if you recall, looked at patients with advanced hepatocellular carcinoma [HCC] and randomized patients to atezolizumab, as an anti—PD-L1 [anti–programmed death-ligand 1], plus bevacizumab, as an antiangiogenic, versus sorafenib as a standard of care.

This study was made available for patients who had advanced liver cancer, either locally advanced, not amenable to local therapy, or metastatic disease, good liver performance, Child-Pugh A scoring, understandably no prior active bleeding by varices. Actually, if I recall, it required 6 months of previous treatment, no action on any varix, or of course, no event within the month that happened before going on the study. So they were very cautious, and make sure that any potential antiangiogenic effect of bevacizumab would not ultimately cause any potential variceal bleeds. This was a very important and key point of the study.

With this said, when the patients were randomized, ultimately it was with the aim of a primary end point being overall survival, but also another primary end point was progression-free survival, which makes sense. Especially with the advent of so many therapies, it made sense to look from different perspectives or use a different set of eyes to look at what the study might do.

What I like the most about the IMbrave150 is that if you look at the demographics of it, it’s really the bread and butter of what we see in clinic. I would say that it is a very similar model to what we have seen, for example, with the SHARP trial, and everything in between. Patients had the median age for liver cancer, like the mid-60s or about; of course, understandably more men than women. The distribution among the ethnicities was very global. Etiologies or risk factors, again, were pretty apparent for all of them. Some people might say, “Oh, maybe a little bit more Asia heavy.” I wouldn’t say necessarily so because, remember, we see hep [hepatitis] B in other parts of the world as well and do have patients of Asian descent in many parts of the world.

There was a distribution of about 80% of patients with BCLC-C [Barcelona clinic liver cancer-stage C], i.e., metastatic disease, and close to 20% or less, BCLC-B, again the same distribution in other studies that we have seen before. This study completed its accrual. It was rather robust, quite impressive, how fast they were able to accrue the study. I would say that what’s impressive is this 2:1 randomization, the outcome of the atezolizumab plus bevacizumab was far better than it was for sorafenib. The overall survival, median overall survival, was not yet evaluable for the atezolizumab plus bevacizumab study, which is nice. At the same time, for the sorafenib, it was about 13 plus months, which is similar to what we have seen in different studies, like for example, the lenvatinib versus sorafenib study.

By the way, the overall survival also was statistically significant. I think the hazard ratio, if I’m not mistaken, was like 0.58 or 0.59, and the P value was like as many 0s as you want, 6 or 1. The progression-free survival was also positive. Maybe you can say I would have expected a little bit more than that, but nonetheless, it’s about 6 months for the ATEZO/BEV [atezolizumab/bevacizumab] versus about 4 months for the sorafenib. Again, clinically and statistically significant with a hazard ratio of 0.58 or 0.59, and the P value was 0.0006, triple zero 6, I recall. Clearly this study was positive. There are no ifs or buts about it.

The secondary end points were multifaceted, and I’m sure we’re going to hear more about that study as it comes out, with more of the same components. But it’s nice to see that the responses were really robust, and we have seen what was defined as CR [complete response], PR [partial response], things that we never heard of in HCC. So these are definitely very nice to hear.

And as far as adverse effects, what we all thought historically is that bevacizumab in its prior experience in liver cancer might lead to a potential increase in bleeding, and this was the first study that was reported in JCO [Journal of Clinical Oncology] on bevacizumab in liver cancer. Surprisingly, not much and, that’s maybe good for the investigators and the sponsor. They really were very careful about putting the true eligibility criteria, i.e., patients without an active bleed, as we said, no prior active bleed for a long time, and it definitely paid back because of the limited or barely accountable amount of bleeding toxicities, especially varices. So I would say all in all, the drug was very well tolerated.

Of course on that point, it would be important to be recognizant that it’s going to be available for all of us in use, to make sure that patients are screened ahead of time, the same way it was on the study with a scope, being evaluated to ensure that they are, of course, appropriately eligible, and it would be safe to give the drugs. And this is a message that I send to all colleagues of ours. No matter what your practice is, if you are thinking of atezolizumab plus bevacizumab therapy, make sure that you send your patients for an endoscopy, at least for screening purposes.

I am using atezolizumab/bevacizumab. Actually, I’ll ask the question to all of us: are we using it? By all means I am because the drugs are now available, and with the data, you can at least attempt with whatever support that the patient has for getting their medical care, to see if they will approve it, and hope that they will.

Because at the end of the day, we cannot deny such good therapy for our patients, even though I do recognize that we have to wait for the completion of the data, even though the study already is in its 19th month, and still we have not crossed the median for the atezolizumab/bevacizumab. Where is it going to be? Even if everything goes bad today, it’s still about 19 months, but of course it’s going to be probably a little bit longer. By all means, this is a positive study. It was very nice, and exciting, and invigorating to see it happening and presented at the ESMO [European Society for Medical Oncology] Asia 2019 annual meeting.

Transcript Edited for Clarity