Post Conference Perspectives: Immunotherapy Combinations for Unresectable HCC - Episode 3

The COSMIC-312 Phase III and Other Notable Trials


Ghassan K. Abou-Alfa, MD: As we said in the beginning, atezolizumab/bevacizumab is not the only combination study that we are looking at or studying as far as combinations. This is atezolizumab as an anti—PD-L1 [anti–programmed death-ligand 1] plus bevacizumab as an antiangiogenic. But there are other combinations, and at least I can, again, bring something else that was reported at the ESMO [European Society for Medical Oncology] Asia 2019 annual meeting, the COSMIC-312 study looking at the combination of cabozantinib plus atezolizumab. This is bringing a different combination, and I would say it’s very important for us not to compare apples and oranges. Cabozantinib is not an antiangiogenic, even though it has an anti-VEGF, but it has anti-AXL, anti-MET, so it’s a lot of other targets. And in combination with atezolizumab, it is going to be very important for us to really figure out what that means. So we’re waiting for the data of this combination. We’ll see where it takes us from there.

Of course, this brings in the question again about what other combinations could be there. I can tell you there are a lot of studies of combinations of different nature, and it’s very important to pay close attention to all of them. Another one along the same line as COSMIC-312 is lenvatinib plus pembrolizumab, a very potent TKI [tyrosine kinase inhibitor], being lenvatinib, plus a very solid anti—PD-1 [anti–programmed cell death protein 1], pembrolizumab, in combination, definitely is again an argument that could be made very comfortably to look at the combination in the phase III trial, which is ongoing.

This brings us to the other type of combination that we’re talking about, as I mentioned in the beginning for discussion, the combination of checkpoint inhibitors. And the one I gave as an example is represented in the HIMALAYA study, which is looking at an anti—PD-L1, being durvalumab, plus anti–CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4], which is tremelimumab, in combination versus single-agent durvalumab, versus single-agent sorafenib.

This study is important because biologically, as much as we have seen that checkpoint inhibitors don’t do much on their own, well they can’t do it on their own because they need some inducer to make it happen. And 2 types of inducers could be there, at least for now, and 1 of them is the combination of an antiangiogenic or anti-TKI. For example, the bevacizumab is capable of enhancing the blocked flow, to the tumor, i.e., the checkpoint inhibitors can get to the tumor. Number 2, it actually will deactivate the checkpoints that will limit the immunotherapy from acting on the tumor. And interestingly, it might even replete some of those immune cells at the completion of the effect of the atezolizumab. So it’s a little bit of a circular thing that happens all along, and that’s really where the value is of the atezolizumab plus bevacizumab.

On the other hand, another thing can be looked at in regard to the anti—CTLA-4 plus anti–PD-L1. As we said, anti–PD-L1 by itself can’t do it, interestingly, because they need to get a call from upstairs from the lymph nodes. As we all know, anti–CTLA-4 is a very important mechanism that will hijack the CTLA-4, so it doesn’t really inhibit the effect of CD80 and CD86, which are induced to cause the effect at the tumor cell level by the anti–PD-1 or anti–PD-L1. And this activity of anti–CTLA-4 would be a very important driver for ultimately the effect of the anti–PD-L1 at the tumor cell level. Regarding the HIMALAYA study, we’ll just have to wait for the data and hopefully see some more positivity as we’ve been seeing for the last few years in regard to liver cancer.

And of course, in all those studies we see that the eligibility criteria are similar, which really makes us able to interpret that data. These patients thankfully we are seeing more and more in clinic, not necessarily that we always have seen them. But now with the advent of that many therapies and options in HCC [hepatocellular carcinoma], we are seeing more of them in the oncology world.

Transcript Edited for Clarity