The science of that is going to come into play, and this is one of the biggest challenges that I am working on at the moment—how to line them up. If CheckMate-459 is positive, and there are other studies coming along—including HIMALAYA, which is a large study looking at the combination of anti–PD-1 plus anti–CTLA-4—patients will expect us to attempt checkpoint inhibitors as a first-line therapy. Then from that point on, you go into the second-line setting, which will be based on TKIs.
How are the TKIs going to be lined up? It will probably be dependent on certain guidances. For example, we know that regorafenib [targets] IGF
and lenvatinib [targets] FGF
. These are going to be certain aspects that we might elaborate further. To be fair, the question is a little bit early because we don’t have the data for cabozantinib yet. For lenvatinib, we have it only for an abstract form. For nivolumab, we have the data but we don’t have it in a phase III trial. There is lots to be covered still, and we will move forward in that regard.
Will more checkpoint inhibitors be explored down the road?
I would take the question a different way. There will be more checkpoint inhibitors but interestingly, for me, I have already decided that TKIs are great. They have really improved outcomes for patients. Now, [more TKIs] are going to be a variation of the same subject. Checkpoint inhibitors are almost [in the same situation] and we already know the lineup of what is going to happen with them.
Other than nivolumab, we have pembrolizumab (Keytruda) which is being looked at in the second-line setting. We have the durvalumab (Imfinzi) and tremelimumab combination in the first-line setting, which is being looked at in the HIMALAYA study. There is no question that we know the caveat of things. What will the combinations be of? Will it be a combination of TKIs plus checkpoint inhibitors? By all means, it will happen.
However, my mindset is somewhere else. The third phase of that effort is going to be more based on local approaches with systemic therapy or more directed immunotherapy. I am very happy to see, and very proud that I am involved in, the effort with Pexa-Vec, which is being looked at as an intratumoral injection on top of sorafenib. We'll see that phase III trial soon. It is ongoing and we will see where it’s going to take us. It is an impressive effort, but the other thing that will have a lot of potential, though we haven’t seen any data yet, will be CAR T-cell therapy. There is no question that there are questions looking at AFP [alpha-fetoprotein]. The question is, “Is AFP the right antigen that we're going a after, or will there be another antigen?”
Going back to regorafenib, what else could we see with this agent?
There are a lot of potentials over here but, so far, the best understanding we have is [its activity with patients who have] prior exposure to sorafenib. Combinations have been tried with sorafenib, but I don’t think there is going to be anything visible as with regorafenib.
In closing, what do you expect we will be reflecting on at the end of 2018?
One year from now, we will no doubt, [be discussing] CheckMate-459; we will hopefully have enough data with regard to pembrolizumab. The HIMALAYA study just started, so it will not be ready by then, but we probably will have some gist about that. More importantly, we will see some efforts regarding answers about the sequencing, and I would like to see more activity from the novel components I mentioned, such as the Pexa-Vec virus or CAR T-cell therapy.