Checkpoint Inhibitors, TKIs, and Novel Agents Poised to Enter Liver Cancer Treatment Paradigm

Ghassan Abou-Alfa, MD

Prior to 2017, the hepatocellular carcinoma (HCC) space had little movement in therapeutic advancements beyond standard sorafenib (Nexavar).

Two more agents have since been added to the treatment landscape: regorafenib (Stivarga) in April and nivolumab (Opdivo) in September, both of which can be administered in patients following treatment with sorafenib.

But other therapies are moving steadily through the pipeline, as well. Lenvatinib (Lenvima) was compared with sorafenib in the phase III Study 304 trial, a noninferiority study that showed no difference between the 2 agents in the frontline setting. Moreover, the phase III CELESTIAL trial exploring cabozantinib (Cabometyx) in patients who previously received sorafenib was announced to have met the primary endpoint of overall survival. Data are likely to be presented at the 2018 Gastrointestinal Cancers Symposium.

“We have a total 4 tyrosine kinase inhibitors (TKIs); 2 of them are already approved and 2 are waiting to be approved,” said Ghassan K. Abou-Alfa, MD. “In addition to that, we have a checkpoint inhibitor and, of course, there is more to come.”

“More to come,” includes the anticipated phase III findings of the Pexa-Vec oncolytic immunotherapy in patients who previously received sorafenib (Nexavar), as well as the early studies starting to explore chimeric antigen receptor (CAR) T-cell therapy in liver cancer.

OncLive^®: A lot has been happening in this field as of late. What would you like to highlight?

In an interview during the 2017 OncLive^® State of the Science SummitTM on Gastrointestinal Cancers, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed what he sees coming down the pike in HCC with regard to novel agents, including CAR T-cell therapy, and the burgeoning questions with optimal sequencing of these treatments.Abou-Alfa: It has been great to be here tonight for the State of the Science SummitTM, and it was a great honor to talk about primary liver cancer, especially this year. This has been an incredible year and positive time regarding our therapies for [patients with] liver cancer. As we both know, liver cancer had only one therapy, sorafenib, that was approved by the FDA almost 10 years ago. If anything, we have been trying for the past 10 years to see how we can improve on the outcome of sorafenib either by trying different things—by going into combination therapies, or even looking at second-line therapy.

Many great efforts have been done and, unfortunately, all of them have been negative. However, this year has been quite impressive. Now, in the second-line setting, regorafenib has been proven to show an improvement in survival compared with placebo after the prior exposure to sorafenib. This is FDA approved.

In addition to that, we have seen incredible data on the advent of checkpoint inhibitors or immunotherapy. Nivolumab has been evaluated in a phase II trial and has shown that the response rate for patients with HCC will be somewhere in the range between 15% and 20%. Based on that limited phase II study, the FDA approved the drug in the second-line setting. Of course, we are awaiting the large phase III trial, Checkmate-459, which will look at nivolumab versus sorafenib in the first-line setting. We'll see where this will take us.

Then, interestingly, the story does not stop there. We have heard about the noninferiority study of lenvatinib, another TKI, which was evaluated versus sorafenib. It was a quite innovative study and more importantly, the study was positive. There was no difference between lenvatinib and sorafenib. If anything, lenvatinib was shown to have other important aspects that are positive regarding response and tolerance. I, personally, would not be surprised if it was FDA approved.

We have talked about 3 drugs, and the fourth one is cabozantinib, a c-MET inhibitor. Our prior experience with c-MET inhibitors, with tivantinib was a negative study and it did not show an improvement in outcomes versus placebo in c-MET—positive patients.

Though it is early, how do you foresee an FDA approval of cabozantinib shaking up the paradigm?

But this time, we took a different perspective with cabozantinib where we allowed all patients to enroll and the trial is positive. We don’t have data yet but, as already announced in the public releases, we expect to present the data at the 2018 Gastrointestinal Cancers Symposium. That is, in brief, where things stand.Actually, this question is very important. It is not only dependent the cabozantinib data; it is going be dependent on many other data, including nivolumab. In other words, how are we going to line up those therapies? [Do you decide by saying things] like, “I like this drug. I’m used to that drug” or “Is [this drug] more tolerated?” There is more to the story.

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.

Will more checkpoint inhibitors be explored down the road?

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.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.

Going back to regorafenib, what else could we see with this agent?

In closing, what do you expect we will be reflecting on at the end of 2018?

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?”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.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.